Triazolopyridine compounds as pim kinase inhibitors

ABSTRACT

Compounds of Formula (I), in which A, B, R 1 , R 1a , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  have the meanings given in the specification, are receptor tyrosine inhibitors useful in the treatment of immune cell-associated diseases and disorders, such as inflammatory and autoimmune diseases.

The present invention relates to novel compounds, to pharmaceuticalcompositions comprising the compounds, to a process for making thecompounds and to the use of the compounds in therapy. More particularly,it relates to certain triazolopyridine compounds useful in the treatmentand prevention of diseases which can be treated with a PIM kinaseinhibitor, including diseases mediated by PIM kinases. Particularcompounds of this invention have been found to be inhibitors of PIM-1and/or PIM-2 and/or PIM-3.

Protein kinases constitute a family of structurally related enzymes thatare responsible for the control of a vast array of cellular processes.

The PIM kinase sub-family consists of three distinct serine/threonineprotein kinase isoforms (PIM-1, -2 and -3) belonging to thecalmodulin-dependent protein kinase-related (CAMK) group. PIM-2 andPIM-3 are respectively 58% and 69% identical to PIM-1 at the amino acidlevel.

The over-expression of PIM-1 has been reported in various humanlymphomas and acute leukemias (Amson, R. et al., Proc. Natl. Acad. Sci.U.S.A., 1989, 86: 8857-8861). PIM-1 has been shown to synergize withc-Myc to drive lymphomagenesis (Breuer M., et. al., Nature, 1989, 340;61-63), and plays an important role in cytokine signaling in T-celldevelopment (Schmidt, T., et. al., EMBO J, 1998, 17:5349-5359). Inaddition, there is evidence that PIM-1 is over-expressed in prostaticneoplasia and human prostate cancer (Valdman, A. et al., The Prostate,2004, 60: 367-371; Cibull, T. L. et al., J. Clin. Pathol., 2006, 59:285-288) and may serve as a useful biomarker in identification ofprostate cancer (Dhanasekaran, S. M. et al, Nature, 2001, 412(13):822-826). PIM-1 has been shown to be critical for IL-6 mediatedproliferation of hematopoietic cells (Hirano, T., et. al. Oncogene 2000,19: 2548-2556), as well as STAT3 mediated cell cycle progression(Shirogane, T., et al., Immunity 1999, 11:709).

Recently, it has been discovered that PIM-1 is up-regulated by Flt-3 andmay play an important role in Flt-3 mediated cell survival (Kim, K. T.et al., Neoplasia, 2005, 105(4): 1759-1767). Since Flt-3 itself isimplicated in leukemias like AML, additional knockdown of PIM-1 may be auseful approach to treating leukemias driven by Flt-3 or variousmutations. Accordingly, PIM-1 inhibitors may be useful as therapeuticagents for a variety of cancers such as hematological cancers.

PIM-2 is a highly conserved serine/threonine kinase involved in cellproliferation and the prevention of apoptosis (Baytel et al., Biochim.Biophys. Acta Gene Struct. Expr. 1442: 274 (1998)). PIM-2 is upregulatedin AML, CLL, and possibly in prostate cancer.

PIM-3 is a proto-oncogene identified in pancreatic liver and coloncancers, and is an apoptotic regulator (Popivanova, B., et al., CancerSci., 98(3): 321 (2007)).

Based upon the direct involvement of the Pim kinases in a wide varietyof cancers downstream of STAT3/5 activation, it is expected thatinhibition of the Pim kinases will result in inhibition of proliferationand survival of multiple cancer cell types. This would then be expectedto provide a therapeutic benefit to cancer patients with a variety ofcancers (both in solid tumor and hematologic settings), as well as otherconditions that are mediated by Pim kinase signaling.

In addition to the malignant cells detailed above, PIM kinases are alsoexpressed in hematopoietically-derived cell lines andhematopoietically-derived primary cells including cells of the immunesystem such as B cells, T cells, monocytes, macrophages, eosinophils,basophils, and dendritic cells. Expression of PIM kinases is induced bycytokines which utilize Jak/Stat signaling, such as IL-2, IL-3,IL-4,IL-5, IL-6, IL-7, IL-9, IL-12, IL-15, GM-CSF, IFNα, IFNγ,erythropoietin, thrombopoietin, and prolactin, and the generation,differentiation, maintenance and activation of hematopoietically-derivedcells is dependent on these cytokines. Moreover, PIM proteins have beenshown to be required for the efficient proliferation of peripheral Tcells mediated by T-cell receptor and IL-2 signaling (Mikkers, et al.,Mol. Cell. Biol., 2004, 6104). Although the exact mechanism of action ofPIM kinases in an immunological setting has yet to be fully defined,they have been reported to phosphorylate a number of substrates involvedin cellular proliferation, differentiation, and survival (Bullock etal., J. Biol. Chem., 2005 280:41675; Chen et al., PNAS 2002 99:2175;Dautry et al., J. Biol. Chem. 1998 263:17615).

Chronic and acute inflammatory and autoimmune diseases are associatedwith the overproduction of pro-inflammatory cytokines and activation ofimmune cells against the body's own tissues. However, many of thesediseases are not adequately treated by current therapies and/or thesetherapies have significant side effects/risks.

A particular example of an autoimmune disease is multiple sclerosis(MS). MS is a progressive central nervous system (CNS) inflammatoryautoimmune disease wherein the immune system mounts responses againstCNS components. The resulting damage to axons and nerves leads toprogressive neurological impairment and significant disability. MSaffects over 2.5 million people worldwide (www.nationalmssociety.org);however many current therapies are only moderately effective and havequestionable risk factors

A need therefore remains for compounds and methods for treatingautoimmune and inflammatory diseases.

International patent application, publication number WO 2004/058769discloses, inter alia, certain 3-aryl and 3-N-arylamino-substituted[1,2,4]triazolo[4,3-b]pyridazines purported to inhibit several proteinkinases, including PIM-1.

International patent application, publication number WO 2008/022164discloses phenyl- and pyridyl-substituted pyrazines and pyridines asPIM-2 inhibitors said to be useful in the treatment of cancer andinflammation.

International patent application, publication number WO 2008/106692,published 4 Sep. 2008 after the first priority date for the presentinvention, discloses carboxamide-substituted pyridines and2-oxopyrimidines which are inhibitors of PIM-1, PIM-2 and PIM-3.

It has now been found that certain [1,2,4]triazole[4,3-a]pyridinecompounds bearing a quinolinyl group at the 3 position of thetriazolopyridine ring are inhibitors of PIM kinases, in particularPIM-1, PIM-2 and/or PIM-3 kinases, which are useful for treatingdiseases such as cancers and inflammatory diseases. In addition,compounds of the invention may be useful for treating immunecell-associated diseases and disorders, such as inflammatory andautoimmune diseases.

Accordingly, provided is a compound of general Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

A is OR¹⁰ or NR¹¹R¹²;

B is H, F, Cl, OR^(a), (1-6C alkyl)NR^(b)R^(c), (1-6C alkyl)OH,CH(OH)CH₂OH, or (1-4C alkyl);

R¹ is H, F, Cl, Br, Me, cyclopropyl or CN;

R^(1a), R², R³ and R⁴ are independently H, F, Cl, Br, Me or CN;

R⁵ and R⁷ are independently H, F, Me or CN;

R⁶ is H, F, Me, Br, CN, cyclopropyl, phenyl, MeO— or MeOCH₂CH₂O—;

R¹⁰ is H, hetCyc¹, -(1-3C alkyl)hetCyc^(1a), hetCyc²,(CR¹⁷R¹⁸)_(p)(CR¹³R¹⁴)CH₂NR¹⁵R¹⁶, —(CR¹⁷R¹⁸)_(p)(CR¹³R¹⁴)CH₂OH, (1-6Calkyl), hetAr¹, (1-3C alkyl)hetAr^(1a), or (3-7C)cycloalkyl substitutedwith NH₂, NH(1-6C alkyl) or N(1-6C alkyl)₂;

R¹¹ is H or (1-6C)alkyl;

R¹² is hetCyc³, (1-6C alkyl)NR¹⁵R¹⁶, C(O)(1-6C alkyl)NR¹⁵R¹⁶, (1-6Calkyl)NHC(O)O(1-6C alkyl), or (4-7C)cycloalkyl optionally substitutedwith OH, NH₂, NH(1-6C alkyl) or N(1-6C alkyl)₂;

R¹³ is H, (1-6C)alkyl, F or OH, and

R¹⁴ is H, (1-6C)alkyl or F, or

R¹³ and R¹⁴ together with the carbon atom to which they are attachedform a 3-6 membered carbocyclic ring;

each R¹⁵, R¹⁶, R¹⁷ and R¹⁸ is independently H or (1-6C)alkyl,

or each R¹⁵, R¹⁷ and R¹⁸ is independently H or (1-6C)alkyl and R¹⁶ is H,(1-6C)alkyl, C(═O)CH₂F, CH₂CHF₂ or CH₂CF₃;

or NR¹⁵R¹⁶ forms a 5-6 membered heterocyclic ring having a first ringheteroatom which is N and optionally having a second ring heteroatomselected from N and O;

hetCyc¹, hetCyc^(1a), and hetCyc³ are independently a 4-7 memberedheterocycle having a ring nitrogen atom and optionally substituted withone or more R⁹ groups, or

hetCyc¹ and hetCyc³ are independently a 4-7 membered heterocycle havinga ring nitrogen atom and optionally substituted with one or more R⁹groups, and hetCyc^(1a) is selected from a morpholinyl and 4-7 memberedazacyclic ring optionally substituted with one or more R⁹ groups;

each R⁹ is independently selected from halogen, (1-6C)alkyl,cyclopropylmethyl, benzyl, NR^(f)R^(g), -(1-6C alkyl)NR^(h)R^(i),OR^(j), (1-6C alkyl)OR^(k), (1-6C)fluoroalkyl, C(O)NR^(m)R^(n), (1-6Calkyl)C(O)NR^(p)R^(q), and C(O)O(1-6C alkyl);

hetCyc² is an 8-membered bridged heterocycle having a ring nitrogenatom;

hetAr¹ and hetAr^(1a) are independently a 5 or 6 membered heteroarylhaving 1-2 ring nitrogen atoms and optionally substituted with one ormore substituents independently selected from F, Cl, Br, Me,cyclopropyl, CN, NH₂, NH(1-6C alkyl) and N(1-6C alkyl)₂;

R^(a) is H, (1-6C alkyl), -(1-6C alkyl)-O-(1-6C alkyl) or -(1-6Calkyl)-O-(3-6C cycloalkyl);

each R^(b), R^(f), R^(g), R^(h), R^(i), R^(k), R^(m), R^(p) and R^(q) isindependently selected from H and (1-6C alkyl);

R^(j) is H, (1-6C alkyl) or cyclopropyl;

R^(n) is H, (1-6C alkyl), —O(1-6C alkyl) or —O(3-6C cycloalkyl); and

p is 0, 1 or 2.

Also provided is a compound of general Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

A is OR¹⁰ or NR¹¹R¹²;

B is H, F, OR^(a), (1-6C alkyl)NR^(b)R^(c), (1-6C alkyl)OH, CH(OH)CH₂OH,or (1-4C alkyl);

R¹ is H, F, Cl, Br, Me, cyclopropyl or CN;

R^(1a), R², R³ and R⁴ are independently H, F, Cl, Br, Me or CN;

R⁵ and R⁷ are independently H, F, Me or CN;

R⁶ is H, F, Me, Br, CN, cyclopropyl or phenyl;

R¹⁰ is H, hetCyc¹, -(1-3C alkyl)hetCyc^(1a), hetCyc²,(CR¹⁷R¹⁸)_(p)(CR¹³R¹⁴)CH₂NR¹⁵R¹⁶, —(CR¹⁷R¹⁸)_(p)(CR¹³R¹⁴)CH₂OH, (1-6Calkyl), hetAr¹, (1-3C alkyl)hetAr^(1a), or (3-7C)cycloalkyl substitutedwith NH₂, NH(1-6C alkyl) or N(1-6C alkyl)₂;

R¹¹ is H or (1-6C)alkyl;

R¹² is hetCyc³, (1-6C alkyl)NR¹⁵R¹⁶, C(O)(1-6C alkyl)NR¹⁵R¹⁶, (1-6Calkyl)NHC(O)O(1-6C alkyl), or (4-7C)cycloalkyl optionally substitutedwith OH, NH₂, NH(1-6C alkyl) or N(1-6C alkyl)₂;

R¹³ is H, (1-6C)alkyl, F or OH, and

R¹¹ is H, (1-6C)alkyl or F, or

R¹³ and R¹⁴ together with the carbon atom to which they are attachedform a 3-6 membered carbocyclic ring;

each R¹⁵, R¹⁶, R¹⁷ and R¹⁸ is independently H or (1-6C)alkyl,

or NR¹⁵R¹⁶ forms a 5-6 membered heterocyclic ring having a first ringheteroatom which is N and optionally having a second ring heteroatomselected from N and O;

hetCyc¹, hetCyc^(1a), and hetCyc³ are independently a 4-7 memberedheterocycle having a ring nitrogen atom and optionally substituted withone or more R⁹ groups;

each R⁹ is independently selected from halogen, (1-6C)alkyl,cyclopropylmethyl, benzyl, NR^(f)R^(g), -(1-6C alkyl)NR^(h)R^(i),OR^(k), (1-6C alkyl)OR^(k), (1-6C)fluoroalkyl, C(O)NR^(m)R^(n), (1-6Calkyl)C(O)NR^(p)R^(q), and C(O)O(1-6C alkyl);

hetCyc² is an 8-membered bridged heterocycle having a ring nitrogenatom;

hetAr¹ and hetAr^(1a) are independently a 5 or 6 membered heteroarylhaving 1-2 ring nitrogen atoms and optionally substituted with one ormore substituents independently selected from F, Cl, Br, Me,cyclopropyl, CN, NH₂, NH(1-6C alkyl) and N(1-6C alkyl)₂;

R^(a) is H, (1-6C alkyl), -(1-6C alkyl)-O-(1-6C alkyl) or -(1-6Calkyl)-O-(3-6C cycloalkyl);

each R^(b), R^(f), R^(g), R^(h), R^(i), R^(k), R^(m), R^(p) and R^(q) isindependently selected from H and (1-6C alkyl);

R^(j) is H, (1-6C alkyl) or cyclopropyl;

R¹¹ is H, (1-6C alkyl), -0(1-6C alkyl) or —O(3-6C cycloalkyl); and

p is 0, 1 or 2.

In certain embodiments, B is selected from any of the values describedabove, other than (1-4C alkyl).

The term “C₁-C₆ alkyl” as used herein refers to saturated linear orbranched-chain monovalent hydrocarbon radicals of one to six carbonatoms, respectively. Examples include, but are not limited to, methyl,ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl,2-methyl-2-propyl, 2,2-dimethylpropyl, 1-pentyl, 2-pentyl, 3-pentyl,2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl,1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl,2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

In certain embodiments, R¹ is H, F or Cl. In certain embodiments, R¹ isH. In certain embodiments, R¹ is F. In certain embodiments, R¹ is Br.

In certain embodiments, R^(1a) is H or F. In certain embodiments, R^(1a)is H.

In certain embodiments, R² is H.

In certain embodiments, R³ is H.

In certain embodiments, R⁴ is H.

In certain embodiments, R⁵ is H.

In certain embodiments, R⁶ is H, F, or Br.

In certain embodiments, R⁶ is CN or Me.

In certain embodiments, R⁶ is phenyl or cyclopropyl.

In certain embodiments, R⁶ is MeO— or MeOCH₂CH₂O—.

In certain embodiments, R⁶ is H.

In certain embodiments, R⁷ is H.

In certain embodiments, each of R², R³, R⁴, R⁵ and R⁷ is H.

In certain embodiments, each of R¹, R^(1a), R², R³, R⁴, R⁵, R⁶ and R⁷ isH.

In certain embodiments, A is OR¹⁰.

In certain embodiments, A is OR¹⁰ where R¹⁰ is represented by theformula hetCyc¹ or (1-3C alkyl)hetCyc^(1a). Particular examples ofhetCyc¹ and hetCyc^(1a) rings include piperidinyl, pyrrolidinyl andazepanyl rings. In certain embodiments, hetCyc¹ and hetCyc^(1a) aresubstituted with one or more R⁹ groups.

Examples of R⁹ groups when represented by halogen include F, Cl and Br.

In certain embodiments, R⁹ is cyclopropylmethyl.

In certain embodiments, R⁹ is benzyl.

Examples of R⁹ groups represented by the formula -(1-6C)alkyl includemethyl, ethyl, propyl and isopropyl.

Examples of R⁹ groups represented by the formula NR^(f)R^(g) includegroups where R^(f) is H or Me and R^(g) is H, methyl, ethyl, propyl,isopropyl, butyl, or isobutyl. Particular values of R⁹ when representedby NR^(f)R^(g) include NH₂ and NHMe.

Examples of R⁹ groups represented by the formula -(1-6Calkyl)NR^(h)R^(i), include groups where R^(h) is H and R^(i) is H or(1-6C)alkyl. Particular values of R⁹ when represented by -(1-6Calkyl)NR^(h)R^(i) include CH₂NR^(h)R^(i), for example CH₂NH₂ andCH₂NHMe.

Examples of R⁹ groups having the formula OR^(j) include groups whereR^(j) is H, (1-6C) alkyl [for example methyl, ethyl, or isopropyl] orcylcopropyl. Particular examples of R⁹ when represented by OR^(j)include OH, OMe and —O-cyclopropyl.

Examples of R⁹ groups represented by the formula (1-6C alkyl)OR^(k)include groups where R^(k) is H or Me. Particular values of suchsubstituents include CH₂OH, CH₂CH₂OH and CH₂OMe.

An example of R⁹ groups represented by the formula (1-6C)fluoroalkylincludes CH₂CH₂F.

Examples of R⁹ groups having the formula C(O)NR^(m)R^(n) include groupswhere R^(m) is H or (1-6C) alkyl (for example H or methyl). In certainembodiments, R¹¹ is H, (1-6C alkyl) or O-(1-6C alkyl), (for example H,methyl or OMe. Particular values of R⁹ include C(O)NH₂ and C(O)NMe(OMe).

Examples of R⁹ groups having the formula (1-6C alkyl)C(O)NR^(p)R^(q)include groups where both R^(p) and R^(q) are hydrogen. In otherembodiments, one of R^(p) and R^(q) is hydrogen and the other is (1-6Calkyl). In other embodiments, both R^(p) and R^(q) are independentlyselected from (1-6C alkyl), for example methyl or ethyl. Particularvalues of R⁹ include CH₂C(═O)NH₂, CH₂CH₂C(═O)NH₂, CH₂C(═O)NHMe andCH₂C(═O)NMe₂.

Examples of R⁹ groups having the formula C(O)O(1-6C alkyl) include CO₂Meand CO₂C(CH₃)₃.

In particular embodiments, hetCyc¹ and hetCyc^(1a) are unsubstituted orsubstituted with one or more R⁹ groups independently selected from F,(1-6C)alkyl, cyclopropylmethyl, benzyl, C(O)O(1-6C)alkyl, (1-6Calkyl)OR^(k), C(O)NR^(m)R^(n), (1-6C alkyl)C(O)NR^(p)R^(q), OR and(1-6C)fluoroalkyl.

In particular embodiments, hetCyc¹ and hetCyc^(1a) are unsubstituted orsubstituted with one or more R⁹ groups independently selected from F,(1-6C)alkyl, cyclopropylmethyl, benzyl, C(O)O(1-6C)alkyl, (1-6Calkyl)OR^(k), C(O)NR^(m)R^(n), (1-6C alkyl)C(O)NR^(p)R^(q) and OR^(j).

In certain embodiments, hetCyc¹ and hetCyc^(1a) are optionallysubstituted with one or more substituents independently selected from F,methyl, ethyl, isopropyl, CO₂Me, CO₂C(CH₃)₃, C(O)NH₂, C(O)N(Me)OMe,CH₂C(═O)NH₂, cyclopropylmethyl, benzyl, CH₂OH, CH₂CH₂OH, OH, OMe, andCH₂CH₂F.

In particular embodiments, hetCyc¹ and hetCyc^(1a) are optionallysubstituted with one or more substituents independently selected from F,methyl, ethyl, isopropyl, CO₂Me, CO₂C(CH₃)₃, C(O)NH₂, C(O)N(Me)OMe,CH₂C(═O)NH₂, cyclopropylmethyl, benzyl, CH₂OH, CH₂CH₂OH, OH, and OMe.

In certain embodiments, each hetCyc¹ and hetCyc^(1a) is independentlyand optionally substituted with one or two R⁹ groups.

In another embodiment, A is OR¹⁰ where R¹⁰ is represented by the formula(I-3C alkyl)hetCyc^(1a) and hetCyc^(1a) is morpholinyl.

Particular embodiments of OR¹⁰ when R¹⁰ is hetCyc¹ or (1-3Calkyl)hetCyc^(1a) include the structures:

Additional examples of OR¹⁰ when R¹⁰ is hetCyc¹ or (1-3Calkyl)hetCyc^(1a) include the structures:

In certain embodiments, A is OR¹⁰ where R¹⁰ is hetCyc². Particularexamples of hetCyc² include bridged heterocyclic ring systems such as8-azabicyclo[3.2.1]octane ring systems. A particular value of OR¹⁰ whenrepresented by —O-hetCyc² includes the structure:

In certain embodiments, A is OR¹⁰ where R¹⁰ is represented by theformula (CR¹⁷R¹⁸)_(p)(CR¹³R¹⁴)CH₂NR¹⁵R¹⁶. In certain embodiments, p is0. In other embodiments, p is 1 or 2. In certain embodiments, R¹⁷ andR¹⁸ are both H. In certain embodiments, R¹⁷ and R¹⁸ are bothindependently selected from a (1-6C alkyl) group, for example methyl,ethyl, propyl and isopropyl. In certain embodiments, one of R¹⁷ and R¹⁸is H and the other is (1-6C alkyl). In certain embodiments, R¹³ and R¹⁴are each H. In certain embodiments, R¹³ and R¹⁴ are each F. In otherembodiments, R¹³ and R¹⁴ are independently H or (1-6C) alkyl, forexample methyl, ethyl, propyl or isopropyl. In other embodiments, R¹³and R¹⁴ together with the carbon atom to which they are attached form acyclopropyl ring. In certain embodiments, R¹⁵ and R¹⁶ are each H. Inother embodiments, R¹⁵ and R¹⁶ are independently H or (1-6C) alkyl, forexample methyl, ethyl, propyl or isopropyl. In certain embodiments, R¹⁷is H. In other embodiments, R¹⁷ is (1-6C alkyl), for example methyl,ethyl, propyl or isopropyl. Particular embodiments of OR¹⁰ whenrepresented by —O—(CR¹⁷R¹⁸)_(p)(CR¹³R¹³)CH₂NR¹⁵R¹⁶ include thestructures:

In certain embodiments, A is OR¹⁰ where R¹⁰ is represented by theformula (CR¹⁷R¹⁸)_(p)(CR¹³T¹⁴)CH₂NR¹⁵R¹⁶ and R¹³ and R¹⁴ together withthe carbon atom to which they are attached form a cyclopentyl ring. Aparticular example is the structure:

In certain embodiments, A is OR¹⁰ where R¹⁰ is represented by theformula (CR¹⁷R¹⁸)_(p)(CR¹³R¹⁴)CH₂NR¹⁵R¹⁶, where each R¹⁵, R¹⁷ and R¹⁸ isindependently H or (1-6C)alkyl and R¹⁶ is H, (1-6C)alkyl, C(═O)CH₂F,CH₂CHF₂ or CH₂CF₃. In certain embodiments, R¹⁵, R¹⁷ and R¹⁸ are H andR¹⁶ is C(═O)CH₂F, CH₂CHF₂ or CH₂CF₃. Particular examples include thestructures:

In certain embodiments, A is OR¹⁰ where R¹⁰ is represented by theformula —(CR¹⁷R¹⁸)_(p)(CR¹³R¹⁴)CH₂OH. In certain embodiments, p is 0. Inother embodiments, p is 1 or 2. In certain embodiments, R¹⁷ and R¹⁸ areboth hydrogen. In certain embodiments, R¹⁷ and R¹⁸ are bothindependently selected from (1-6C alkyl), for example independentlyselected from methyl, ethyl and propyl. In certain embodiments, one ofR¹⁷ and R¹⁸ is hydrogen and the other is selected from (1-6C alkyl). Incertain embodiments, R¹³ and R¹⁴ are each H. In certain embodiments, R¹³and R¹⁴ are each independently selected from a (1-6C)alkyl group, suchas methyl, ethyl, propyl or isopropyl. In other embodiments, R¹³ is OH,and R¹⁴ is H. In other embodiments, R¹³ and R¹⁴ together with the atomto which they are attached form a 3-6 membered carbocycle, for example acyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring. Particularembodiments of OR¹⁰ when represented by —O—(CR¹⁷R¹⁸)_(p)(CR¹³R¹⁴)CH₂OHinclude the structures:

In certain embodiments, A is OR¹⁰ where R¹⁰ is (1-6C alkyl). Particularexamples of OR¹⁰ include the structures:

In certain embodiments, A is OR¹⁰ where R¹⁰ is (3-7C)cycloalkylsubstituted with a substituent selected from NH₂, NH(1-6C alkyl) orN(1-6C alkyl)₂, for example NH₂, NHMe or NMe₂. A particular value ofOR¹⁰ when R¹⁰ is (3-6C)cycloalkyl includes the structure:

In certain embodiments, A is OR¹⁰ where R¹⁰ is hetAr¹ or(1-3Calkyl)hetAr^(1a). Examples of hetAr¹ and hetAr^(1a) include pyridyland pyrimidyl rings optionally substituted with C₁ or NH₂. Particularvalues of OR¹⁰ when R¹⁰ is hetAr¹ or (1-3Calkyl)hetAr^(1a) include thestructures:

In certain embodiments, A is OH.

In certain embodiments, A is NR¹¹R¹².

In certain embodiments, A is NR¹¹R¹², wherein R¹² is hetCyc³ optionallysubstituted with one or more R⁹ groups described hereinabove. Particularexamples of hetCyc³ include piperidinyl and pyrrolidinyl rings. Incertain embodiments, hetCyc³ is substituted with one or more R⁹ groupsindependently selected from (1-6C) alkyl. In certain embodiments, R¹¹ isH. Particular examples of NR¹¹R¹² when R¹² is hetCyc³ include thestructures:

In certain embodiments, A is NR¹¹R¹² and R¹² is (1-6C alkyl)NR¹⁵R¹⁶. Incertain embodiments, R¹¹ is H. In certain embodiments, R¹⁵ and R¹⁶ areeach H. In certain embodiments, R¹⁵ is H and R¹⁶ is (1-6C)alkyl, forexample methyl, ethyl, propyl or isopropyl. In certain embodiments,NR¹⁵R¹⁶ forms a 5-6 membered heterocyclic ring having a first ringheteroatom which is N and optionally having a second ring heteroatomselected from N and O. Examples of heterocyclic rings includepyrrolidinyl, piperidinyl, piperazinyl and morpholinyl. Particularembodiments of NR¹¹R¹² include the structures:

In certain embodiments, A is NR¹¹R¹², wherein R¹² is C(O)(1-6Calkyl)NR¹⁵R¹⁶. In certain embodiments, R¹¹ is H. In certain embodiments,R¹⁵ and R¹⁶ are each H. In certain embodiments, R¹⁵ is H and R¹⁶ is(1-6C)alkyl, for example methyl, ethyl, propyl or isopropyl. In certainembodiments, NR¹⁵R¹⁶ forms a 5-6 membered heterocyclic ring having afirst ring heteroatom which is N and optionally having a second ringheteroatom selected from N and O. Examples of heterocyclic rings includepyrrolidinyl, piperidinyl, piperazinyl and morpholinyl. A particularvalue of NR¹¹R¹² is NHC(O)CH₂CH₂NH₂.

In certain embodiments, A is NR¹¹R¹², wherein R¹² is (1-6 Calkyl)NHC(O)O(1-6C alkyl), for example (1-6 C alkyl)NHC(O)OC(CH₃)₃. Incertain embodiments, R¹¹ is H. A particular value of NR¹¹R¹²is(CH₂)₃NHCO₂C(CH₃)₃.

In certain embodiments, A is NR¹¹R¹², wherein R¹² is (4-7C)cycloalkylsubstituted with a substituent selected from OH, NH₂, NH(1-6C alkyl) orN(1-6C alkyl)₂. In certain embodiments, R¹¹ is H. A particular exampleof A is the structure:

In certain embodiments, B is H.

In certain embodiments, B is F.

In certain embodiments, B is OR^(a).

Examples of OR^(a) when R^(a) is represented by (1-6C)alkyl include OMe,OEt and O-(isobutyl). A particular value of B when represented by OR^(a)is OMe.

Examples of OR^(a) when R^(a) is represented by -(1-6C alkyl)-O-(1-6Calkyl) include —OCH₂CH₂OMe and —OCH₂CH₂CH₂OMe. A particular value of Bwhen represented by OR^(a) is —OCH₂CH₂OMe.

In certain embodiments, B is (1-6C alkyl)NR^(b)R^(c). In certainembodiments, R^(b) is H and R^(c) is H or (1-6C)alkyl. Particular valuesof B include groups having the formula CH₂NR^(b)R^(c), for exampleCH₂NHEt and CH₂NH₂.

In certain embodiments, B is (1-6C alkyl)OH. A particular value of B isCH₂OH.

In certain embodiments, B is CH(OH)CH₂OH.

In certain embodiments, B is (1-4C alkyl). A particular example ismethyl.

It will be appreciated that certain compounds according to the inventionmay contain one or more centers of asymmetry and may therefore beprepared and isolated in a mixture of isomers such as a racemic mixture,or in an enantiomerically pure form.

It will further be appreciated that the compounds of Formula I or theirsalts may be isolated in the form of solvates, and accordingly that anysuch solvate is included within the scope of the present invention.

The compounds of Formula I include pharmaceutically acceptable saltsthereof. In addition, the compounds of Formula I also include othersalts of such compounds which are not necessarily pharmaceuticallyacceptable salts, and which may be useful as intermediates for preparingand/or purifying compounds of Formula I and/or for separatingenantiomers of compounds of Formula I.

Examples of salts of Formula I include acid addition salts, includingsalts of inorganic and organic acids. Particular mention is made ofhydrochloride and trifluoroacetate salts of Formula I.

According to another aspect, the present invention provides a processfor the preparation a compound of Formula I or a salt thereof as definedherein which comprises:

(a) for a compound of Formula I wherein A is NR¹¹R¹², coupling acorresponding compound having the formula II

wherein L¹ represents a leaving atom or group, with a compound havingthe formula HNR¹¹R¹², using a palladium (II) catalyst and a ligand inthe presence of a base; or

(b) reacting a compound of Formula III

with a compound having the Formula IV

in the presence of an organo hypervalent iodine reagent; or

(c) for a compound of Formula I wherein A is OR¹⁰, coupling acorresponding compound having the Formula V

with a compound having the formula HO—R¹⁰ in the presence of a couplingagent and triphenylphosphine in a suitable solvent; or

(d) for a compound of Formula I wherein B is (CH₂)NR^(b)R^(c), reactinga corresponding compound having the Formula VI

with hydrazine; or

(e) for a compound of Formula I where B is OR^(a), reacting acorresponding compound having the Formula VII

with a compound of the formula R^(a)—L², wherein L² represents a leavingatom or group, in the presence of a base; and

removing any protecting group or groups and, if desired, forming a salt.

Referring to method (a), the leaving atom L¹ may be, for example ahalogen atom such as Br or I. Alternatively, L¹ can be a leaving group,such as a hydrocarbylsulfonyloxy group, for example, a triflate group,or an arylsulfonyloxy group or an alkylsulfonyloxy group, such as amesylate or a tosylate group. Suitable palladium catalysts includePd₂(dba)₃ and Pd(OAc)₂. Suitable ligands include rac-BINAP or DIPHOS.The base may be, for example, an alkali metal carbonate or alkoxide,such as for example cesium carbonate or sodium tert-butoxide. Convenientsolvents include aprotic solvents such as ethers (for exampletetrahydrofuran or p-dioxane) or toluene. Alternatively, the reactioncan be performed in the absence of a solvent. The coupling of a compoundof formula (II) with HNR¹¹R¹² can be conveniently performed at atemperature between 0° C. and reflux, and more particularly at reflux,for example at 100° C.

Referring to method (b), the organo hypervalent iodine reagent refers toany hypervalent iodine reagent suitable for forming heterocyclic rings.Examples include iodobenzene diacetate (IBD) and[hydroxy(tosyloxy)iodo]benzene (HTIB), which can be prepared by treatingIBD with p-toluenesulfonic acid monohydrate in acetonitrile. Suitablesolvent systems when using IBD include methanolic potassium hydroxide.Suitable solvent systems when using HT1B include neutral solvents, forexample acetonitrile or dioxane. The reaction can be performed at atemperature ranging from 80 to 110° C.

Referring to method (c), the coupling reagent may be any suitablereagent(s) known to those skilled in the art, for example, DEAD andPPh₃. Convenient solvents include aprotic solvents such as ethers (forexample tetrahydrofuran). The reaction can be conveniently performed ata temperature ranging from −78 to 100° C.

Referring to method (d), the reaction is conveniently performed atambient temperature. Suitable solvents include alcohols such asmethanol.

Referring to method (e), the leaving atom L² may be, for example ahalogen atom such as Br, Cl or I. Alternatively, L² can be a leavinggroup, for example an arylsulfonyloxy group or an alkylsulfonyloxygroup, such as a mesylate or a tosylate group. The base may be, forexample, an alkali metal hydride or carbonate, such as sodium hydride,potassium hydride, sodium carbonate, potassium carbonate or cesiumcarbonate. Convenient solvents include aprotic solvents such as ethers(for example tetrahydrofuran or p-dioxane), DMF, or acetone. Thereaction can be conveniently performed at a temperature ranging from −78to 100° C.

A compound of Formula II

can be prepared by cyclizing a corresponding compound having the formulaVIII

where P¹ is an alcohol protecting group, in the presence of an organohypervalent iodine reagent as described above, followed by deprotectionof the alcohol group and conversion of the alcohol group to analkylsulfonyloxy group, such as a mesylate or a tosylate group.

A compound of Formula VI can be prepared by reducing a correspondingaldehyde having the formula IX

to the corresponding alcohol, followed by reacting the alcohol withisoindoline-1,3-dione in the presence of triphenylphosphine.

The compounds of the formulas (II), (V), (VI), (VIII) and (IX) arebelieved to be novel and are provided as further aspects of theinvention.

The compounds of Formula I include compounds of Formula Ia

and pharmaceutically acceptable salts thereof, wherein:

A is OR¹⁰;

B is H, —CH₂NH₂, —OMe, —OCH₂CH₂OMe, F, Cl or Me;

R¹ is H, F, Cl, Br, Me, cyclopropyl or CN;

R^(1a), R², R³ and R⁴ are independently H, F, Cl, Br, Me or CN;

R⁵ and R⁷ are independently H, F, Me or CN;

R⁶ is H, F, Me, Br, CN, cyclopropyl, phenyl, —OMe, or —OCH₂CH₂OMe;

R¹⁰ is hetCyc¹, -(1-3C alkyl)hetCyc^(1a) or hetCyc²;

hetCyc¹ is a 4-7 membered heterocycle having a ring nitrogen atom andoptionally substituted with one or more R⁹ groups;

hetCyc^(1a) is selected from a morpholinyl and 4-7 membered azacyclicring optionally substituted with one or more R⁹ groups;

each R⁹ is independently selected from halogen, (1-6C)alkyl,cyclopropylmethyl, OR^(j), (1-6C alkyl)OR^(k), (1-6C)fluoroalkyl,C(O)NR^(m)R^(n), (1-6C alkyl)C(O)NR^(p)R^(q), and C(O)O(1-6C alkyl);

hetCyc² is an 8-membered bridged heterocycle having a ring nitrogenatom;

each R^(k), R^(m), R^(p) and R^(q) is independently selected from H and(1-6C alkyl);

R^(j) is H, (1-6C alkyl) or cyclopropyl;

R^(n) is H, (1-6C alkyl), —O(1-6C alkyl) or —O(3-6C cycloalkyl); and

p is 0, 1 or 2.

In certain embodiments of Formula Ia, each of R¹, R², R³, R⁵ and R⁷ ishydrogen.

In certain embodiments of Formula Ia, B is hydrogen.

In certain embodiments of Formula Ia, R¹⁰ is hetCyc¹ or -(1-3Calkyl)hetCyc^(1a).

In certain embodiments of Formula Ia, hetCyc¹ and -(1-3Calkyl)hetCyc^(1a) are optionally substituted with one or two R⁹ groupsindependently selected from Me, Et, isopropyl, cyclopropylmethyl, F, OH,OMe, CH₂OH, CH₂CH₂OH, CH₂CH₂F, CH₂OMe, C(═O)OMe, C(═O)NH₂ andCH₂C(═O)NH₂.

The compounds of Formula I include compounds of Formula Ib

and pharmaceutically acceptable salts thereof, wherein:

A is OR¹⁰;

B is H, —CH₂NH₂, —OMe, —OCH₂CH₂OMe, F, Cl or Me;

R¹ is H, F, Cl, Br, Me, cyclopropyl or CN;

R^(1a), R², R³ and R⁴ are independently H, F, Cl, Br, Me or CN;

R⁵ and R⁷ are independently H, F, Me or CN;

R⁶ is H, F, Me, Br, CN, cyclopropyl or phenyl;

R¹⁰ is H, (CR¹⁷R¹⁸)_(p)(CR¹³R¹⁴)CH₂NR¹⁵R¹⁶,—(CR¹⁷R¹⁸)_(p)(CR¹³R¹⁴)CH₂OH, (1-6C alkyl), or a (3-7C)cycloalkyl ringsubstituted with NH₂, NH(1-6C alkyl) or N(1-6C alkyl)₂;

R¹³ is H, (1-6C)alkyl, F or OH, and

R¹⁴ is H, (1-6C)alkyl or F, or

R¹³ and R¹⁴ together with the carbon atom to which they are attachedform a 3-6 membered carbocyclic ring;

each R¹⁵, R¹⁷ and R¹⁸ is independently H or (1-6C)alkyl;

R¹⁶ is H, (1-6C)alkyl, C(═O)CH₂F, CH₂CHF₂ or CH₂CF₃; and

p is 0, 1 or 2.

In certain embodiments of Formula Ib, each of R¹, R², R³, R⁵ and R⁷ ishydrogen.

In certain embodiments of Formula Ib, B is hydrogen.

The compounds of Formula I include compounds of Formula Ic

and pharmaceutically acceptable salts thereof, wherein:

A is NR¹¹R¹²;

B is H, —CH₂NH₂, —OMe, —OCH₂CH₂OMe, F, Cl or Me;

R¹ is H, F, Cl, Br, Me, cyclopropyl or CN;

R^(1a), R², R³ and R⁴ are independently H, F, Cl, Br, Me or CN;

R⁵ and R⁷ are independently H, F, Me or CN;

R⁶ is H, F, Me, Br, CN, cyclopropyl, phenyl, MeO— or MeOCH₂CH₂O—;

R¹¹ is H or (1-6C)alkyl;

R¹² is hetCyc³;

hetCyc³ is a 4-7 membered heterocycle having a ring nitrogen atom andoptionally substituted with one or more R⁹ groups;

each R⁹ is independently selected from (1-6C)alkyl; and

p is 0, 1 or 2.

In certain embodiments of Formula Ic, each of R¹, R², R³, R⁵ and R⁷ ishydrogen.

In certain embodiments of Formula Ic, B is hydrogen.

The compounds of Formula I include compounds of Formula Id

and pharmaceutically acceptable salts thereof, wherein:

A is NR¹¹R¹²;

B is H, —CH₂NH₂, —OMe, —OCH₂CH₂OMe, F, Cl or Me;

R¹ is H, F, Cl, Br, Me, cyclopropyl or CN;

R^(1a), R², R³ and R⁴ are independently H, F, Cl, Br, Me or CN;

R⁵ and R⁷ are independently H, F, Me or CN;

R⁶ is H, F, Me, Br, CN, cyclopropyl, phenyl, MeO— or MeOCH₂CH₂O—;

R¹¹ is H or (1-6C)alkyl;

R¹² is (1-6C alkyl)NR¹⁵R¹⁶, C(O)(1-6C alkyl)NR¹⁵R¹⁶, (1-6Calkyl)NHC(O)O(1-6C alkyl), or (4-7C)cycloalkyl optionally substitutedwith OH, NH₂, NH(1-6C alkyl) or N(1-6C alkyl)₂; and

each R¹⁵, R¹⁷ R¹⁶ and R¹⁸ is independently H or (1-6C)alkyl.

In certain embodiments of Formula Ic, each of R¹, R², R³, R⁵ and R⁷ ishydrogen.

In certain embodiments of Formula Ic, B is hydrogen.

The ability of test compounds to act as PIM-1, PIM-2 and/or PIM-3inhibitors may be demonstrated by the assay described in Examples A, B,and C, respectively.

Compounds of Formula I have been found to be inhibitors of PIM-1 and/orPIM-2 and/or PIM-3, and are useful for treating diseases and disorderswhich can be treated with a Pim-1 and/or Pim-2 and/or Pim-3 kinaseinhibitor, including diseases mediated by Pim-1 and/or Pim-2 and/orPim-3 kinases. Particular compounds of this invention are inhibitors ofPim-1 and therefore are useful in treating diseases and disordersmediated by Pim-1, such as cancers, such as hematological cancers andsolid tumors (e.g., breast cancer, colon cancer, gliomas).

Examples of hematological cancers include, for instance, leukemias,lymphomas (non-Hodgkin's lymphoma), Hodgkin's disease (also calledHodgkin's lymphoma), and myeloma, for instance, acute lymphocyticleukemia (ALL), acute myeloid leukemia (AML), acute promyelocyticleukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloidleukemia (CML), chronic neutrophilic leukemia (CNL), acuteundifferentiated leukemia (AUL), anaplastic large-cell lymphoma (ALCL),promyelocytic leukemia (PML), juvenile myelomonocyctic leukemia (JMML),adult T-cell ALL, AML with trilineage myelodysplasia (AML/TMDS), mixedlineage leukemia (MLL), myelodysplastic syndromes (MDSs),myeloproliferative disorders (MPD), and multiple myeloma. Additionalexamples of hematological cancers include myeloproliferative disorders(MPD) such as polycythemia vera (PV), essential thrombocytopenia (ET)and idiopathic primary myelofibrosis (IMF/IPF/PMF). Certain cancerswhich can be treated with compounds of Formula I are cancers which arederived from T cells or B cells.

A further embodiment of this invention provides a compound of Formula Ior a pharmaceutically acceptable salt thereof, for use in the treatmentof cancer.

Accordingly, a further embodiment of this invention provides a method oftreating cancer in a mammal in need thereof, comprising administering tosaid mammal a compound of Formula I or a pharmaceutically acceptablesalt thereof. In one embodiment, the cancer is a hematological cancer.In one embodiment, the cancer derives from T cells. In one embodiment,the cancer derives from B cells.

A further embodiment of this invention provides a compound of Formula Ior a pharmaceutically acceptable salt thereof, for use in the treatmentof cancer. In one embodiment, the cancer is a hematological cancer. Inone embodiment, the cancer derives from T cells. In one embodiment, thecancer derives from B cells.

Expression of PIM kinases in immune cells is induced by cytokinespresent during immune responses. Immune cells are critically dependenton cytokines for differentiation and development of effector functionsduring normal and pathogenic immune responses. Thus, compounds of theinvention may be useful for treating diseases and disorderscharacterized by aberrant cytokine production and responses and/oraberrant immune cell activation.

Accordingly, another embodiment of the invention provides a method oftreating diseases and disorders characterized by aberrant cytokineproduction and responses and/or aberrant immune cell activation in amammal in need thereof, comprising administering to the mammal acompound of Formula I or a pharmaceutically acceptable salt thereof.Examples of such diseases and disorders include autoimmune andinflammatory diseases.

Another embodiment provides a compound of Formula I or apharmaceutically acceptable salt thereof for use in the treatment ofdiseases and disorders characterized by aberrant cytokine production andresponses and/or aberrant immune cell activation in a mammal. Examplesof such diseases and disorders include autoimmune and inflammatorydiseases.

Particular examples of diseases and disorders which can be treated usinga compound of Formula I include transplant rejection and autoimmunediseases and disorders. Examples of autoimmune diseases and disordersinclude multiple sclerosis, systemic lupus erythematosis, inflammatorybowel disease (IBD), Crohn's disease, irritable bowel syndrome,pancreatitis, ulcerative colitis, diverticulosis, Grave's disease,arthritis (including rheumatoid arthritis, juvenile rheumatoidarthritis, osteoarthritis, psoriatic arthritis and ankylosingspondylitis), myasthenia gravis, vasculitis, autoimmune thyroiditis,dermatitis (including atopic dermatitis and eczematous dermatitis),psoriasis, scleroderma, asthma, allergy, systemic sclerosis, vitiligo,grave vs. host disease (GVHD), Sjogren's syndrome, glomerulonephritis,IgA nephoropathy, and diabetes mellitus (type I).

As described in further detail in Example E, compounds of Formula I werefound to be effective in inhibiting the proliferation of T cells, aswell as inhibiting cytokine production by T cells stimulated through Tcell receptors and by cytokines in vitro. The effect of these compoundson IL-4 production and IL-22 production supports the utility ofcompounds of Formula I in treating diseases where these cytokines havebeen shown to play a role. Particular examples of such diseases includeasthma, MS and inflammatory bowel disease (IBD), lupus, psoriasis andrheumatoid arthritis.

As an extension of the in vitro data, a compound of Formula I was foundto be effective at inhibiting the generation of T cells responses toantigen in vivo as assessed by proliferation and cytokine production exvivo (Example F). Since T cell activation or proliferation and cytokineproduction are often key components of autoimmune diseases, the dataprovided in Example F supports the utility of compounds of Formula I intreating diseases associated with T cell proliferation and cytokineproduction, including autoimmune diseases such as those describedherein.

B cells are also critically dependent on cytokines for production ofparticular types of immunoglobulins, called antibody (Ab) isotypes, in aprocess referred to as isotype switching. Over time, isotype switchingcan be observed in mice which have been immunized with proteins toproduce antibodies, which can then be quantified (Shi et al, 1999Immunity 10:197-206). As demonstrated in Example G, a compound ofFormula I was found to be effective at inhibiting the production ofcytokine-stimulated Ab isotypes in response to protein immunization.This suggests that compounds of Formula I affect B cells and supportstheir use in treating autoimmune and inflammatory diseases, includingdiseases thought to be associated in part by pathogenic B cell and Abresponses. Examples of such diseases include lupus, multiple sclerosisand rheumatoid arthritis.

As demonstrated in Example H, a compound of Formula I was found to beeffective in a T cell-mediated murine model of experimental autoimmuneencephalomyelitis (EAE). Furthermore, as shown in Example I, a compoundof Formula I was found to be effective in a second EAE model in whichthe disease is caused by generating an immune response to a centralnervous system (CNS) protein. EAE mimics many of the pathologicalfeatures of multiple sclerosis (MS), and these models are widely used tomodel human disease and its treatment.

T cells also play in role in the inflammatory bowel disease (IBD), whichis an autoimmune disease. As demonstrated in Example J, a compound ofFormula I was shown to be effective in a T cell-mediated model of thisdisease.

Lupus is an autoimmune disease characterized by aberrant T and B cellresponses. In particular, lupus patients can exhibit elevated cytokinelevels and increased amounts of anti-nuclear antibodies (Abs). In lupus,Abs can deposit in the kidneys and mediate tissue damage resulting innephritis. In the MRL/lpr mouse, a murine model of lupus, a compound ofFormula I was shown to decrease the production of anti-DNA Abs as wellas decrease proteinuria, a measure of kidney damage (Example K).

Taken together, these examples show that a compound of Formula I iseffective at preventing T cell responses both in vitro and in vivo and Bcell responses in vivo. Further, this concept is put into practice byshowing efficacy of a compound of Formula I in animal models of multiplesclerosis, inflammatory bowel disease and lupus, diseases thought to beassociated in part with aberrant immune cell responses. These datasupport the utility of compounds of Formula I in treating diseasesassociated with immune cells, such as autoimmune and inflammatoryconditions.

Accordingly, certain compounds according to the present invention may beuseful for the treatment of inflammatory disorders mediated by T and Bcells function, such as rheumatoid arthritis, lupus, multiple sclerosis,and inflammatory bowel disease.

Another embodiment of this invention provides a method of treating orpreventing inflammatory and autoimmune diseases, comprisingadministering to a mammal in need thereof an effective amount of acompound of Formula I. Examples of diseases which can be treated includeinflammatory or autoimmune diseases. In one embodiment, the disease ismultiple sclerosis. In another embodiment, the disease is lupus. Inanother embodiment, the disease is inflammatory bowel disease.

A further embodiment of this invention provides a compound of Formula Ifor use in treating an inflammatory or autoimmune disease. In oneembodiment, the disease is multiple sclerosis. In another embodiment,the disease is lupus. In another embodiment, the disease is inflammatorybowel disease.

A subset of the triazolopyridine compounds disclosed herein was found tohave IC₅₀ values for Pim-1 that are at least 10 fold less than the IC₅₀values for Pim-2. As a further example, particular triazolopyridinecompounds disclosed herein were found to have IC₅₀ values for Pim-1 thatare at least 100 fold less than the IC₅₀ for Pim-2. Accordingly, alsoprovided are triazolopyridine compounds which are highly potent Pim-1inhibitors and are highly selective for Pim-1 relative to Pim-2.

A subset of the triazolopyridine compounds disclosed herein were foundto have an IC₅₀ values for Pim-1 that are at least 10 fold less than theIC₅₀ values for Pim-2 and IC₅₀ values for Pim-3 approximately equivalentto that observed for Pim-1. As a further example, particulartriazolopyridine compounds disclosed herein were found to have IC₅₀values for Pim-1 that are at least 100 fold less than the IC₅₀ valuesfor Pim-2, and IC₅₀ values for Pim-3 approximately equivalent to thatobserved for Pim-1. Accordingly, also provided are triazolopyridinecompounds which are highly potent Pim-1/Pim-3 dual inhibitors and arehighly selective for Pim-1 and Pim-3 relative to Pim-2.

As used herein, the term treatment includes prophylaxis as well astreatment of an existing condition.

Accordingly, another aspect of this invention provides a method oftreating diseases or medical conditions in a mammal mediated by a Pim-1and/or Pim-2 and/or Pim-3 kinase, comprising administering to saidmammal one or more compounds of Formula I or a pharmaceuticallyacceptable salt or prodrug thereof in an amount effective to treat orprevent said disorder.

Compounds of Formula I may also be useful as adjuvants to cancertreatment, that is, they can be used in combination with one or moreadditional drugs, for example a chemotherapeutic that works by the sameor by a different mechanism of action.

Compounds of the present invention may also be used in combination withone or more additional drugs, for example an anti-inflammatory compound,an immunosuppressive compound or an immunodepleting agent that works bythe same or a different mechanism of action.

The phrase “effective amount” means an amount of compound that, whenadministered to a mammal in need of such treatment, is sufficient to (i)treat or prevent a particular disease, condition, or disorder mediatedby a Pim-1 and/or Pim-2 and/or Pim-3 kinase, (ii) attenuate, ameliorate,or eliminate one or more symptoms of the particular disease, condition,or disorder, or (iii) prevent or delay the onset of one or more symptomsof the particular disease, condition, or disorder described herein.

The amount of a compound of Formula I that will correspond to such anamount will vary depending upon factors such as the particular compound,disease condition and its severity, the identity (e.g., weight) of themammal in need of treatment, but can nevertheless be routinelydetermined by one skilled in the art.

As used herein, the term “mammal” refers to a warm-blooded animal thathas or is at risk of developing a disease described herein and includes,but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters,and primates, including humans.

Compounds of the invention may be administered by any convenient route,e.g. into the gastrointestinal tract (e.g. rectally or orally), thenose, lungs, musculature or vasculature, or transdermally or dermally.Compounds may be administered in any convenient administrative form,e.g. tablets, powders, capsules, solutions, dispersions, suspensions,syrups, sprays, suppositories, gels, emulsions, patches etc. Suchcompositions may contain components conventional in pharmaceuticalpreparations, e.g. diluents, carriers, pH modifiers, sweeteners, bulkingagents, and further active agents. If parenteral administration isdesired, the compositions will be sterile and in a solution orsuspension form suitable for injection or infusion. Such compositionsform a further aspect of the invention.

According to another aspect, the present invention provides apharmaceutical composition, which comprises a compound of Formula I or apharmaceutically acceptable salt thereof, as defined hereinabove. In oneembodiment, the pharmaceutical composition includes the compound ofFormula I together with a pharmaceutically acceptable diluent orcarrier.

According to another aspect, the present invention provides a compoundof Formula I or a pharmaceutically acceptable salt thereof, for use intherapy, such as the treatment of a Pim-1 and/or Pim-2 and/or Pim-3kinase-mediated condition.

According to a further aspect, the present invention provides the use ofa compound of Formula I, or a pharmaceutically acceptable salt thereof,for use in the treatment of a Pim-1 and/or Pim-2 and/or Pim-3kinase-mediated condition, as defined hereinabove.

Particular compounds of the invention include:

-   2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-N-(piperidin-4-yl)quinolin-8-amine    di-trifloroacetate;-   2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)quinolin    amine;

(trans)-4-(2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)quinolin-8-ylamino)cyclohexanol;

-   (S)-2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-N-(pyrrolidin-3-yl)quinolin-8-amine;-   (R)-2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-N-(pyrrolidin-3-yl)quinolin-8-amine;-   tert-Butyl    3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ylamino)propylcarbamate;

N1-(2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)quinolin-8-yl)propane-1,3-diamine;

N1-(2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)quinolin-8-yl)-N1-isopentylpropane-1,3-diamine;

-   2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(piperidin-4-yloxy)quinoline;-   3-(2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)propan-1-amine;-   (R)-2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-8-(pyrrolidin-3-yloxy)quinoline;-   (S)-2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-8-(pyrrolidin-3-yloxy)quinoline;-   (2S,4S)-Methyl    4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)piperidine-2-carboxylate;-   2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-8-(piperidin-4-ylmethoxy)quinoline;-   2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-8-(2-(piperidin-2-yl)ethoxy)quinoline;-   2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-8-(piperidin-3-ylmethoxy)quinoline;-   (trans)-4-(2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)cyclohexanamine;-   3-(2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethylpropan-1-amine;-   3-(2-(7-(aminomethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethylpropan-1-ol;-   (3-(8-isobutoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanamine;-   3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-N,N,2,2-tetramethylpropan-1-amine;-   (1-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)cyclopropyl)methanol;-   2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(neopentyloxy)quinoline;-   3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethylpropan-1-ol;-   2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((trans)-3-fluoropiperidin-4-yloxy)quinoline;-   2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((cis)-3-fluoropiperidin-4-yloxy)quinoline;-   3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-N-ethyl-2,2-dimethylpropan-1-amine;-   3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-N,2,2-trimethylpropan-1-amine;-   8-(8-azabicyclo[3.2.1]octan-3-yloxy)-2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline;-   (2S)-3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2-ethylpentan-1-amine;-   (2R)-3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2-ethylpentan-1-amine;-   (2S)-3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2-ethylbutan-1-amine;-   (2R)-3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2-ethylbutan-1-amine;-   (2S)-3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2-ethylhexan-1-amine;

(2R)-3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2-ethylhexan-1-amine;

-   (2S,4R)-methyl    4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)pyrrolidine-2-carboxylate;-   2-(7-(2-methoxyethoxy)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol;-   2-(7-methoxy-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol;-   3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yloxy)-2,2-dimethylpropan-1-amine;-   4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)piperidine-1-carboxamide;-   3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-difluoropropan-1-amine;

(cis)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)cyclohexanamine;

-   3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-5-fluoroquinolin-8-yloxy)-2,2-dimethylpropan-1-amine;-   2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(pyridin-3-ylmethoxy)quinoline;-   2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(pyridin-4-ylmethoxy)quinoline;-   2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(5-fluoroazepan-4-yloxy)quinoline;-   Stereoisomer #1 of    2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(−5-fluoroazepan-4-yloxy)quinoline;-   Stereoisomer #2 of    2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(5-fluoroazepan-4-yloxy)quinoline;-   Stereoisomer #3 of    2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(5-fluoroazepan-4-yloxy)quinoline;-   Stereoisomer #4 of    2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(5-fluoroazepan-4-yloxy)quinoline;-   2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(-3-fluoroazepan-4-yloxy)quinoline;-   2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(azepan-4-yloxy)quinoline;-   (2S,4S)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic    acid;-   (2S,4S)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-N,N-dimethylpiperidine-2-carboxamide;-   (2S,4S)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-N-methoxy-N-methylpiperidine-2-carboxamide;-   ((2S,4S)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)piperidin-2-yl)methanol;-   2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-842S,4S)-2-(methoxymethyl)piperidin-4-yloxy)quinoline;-   3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-7-bromoquinolin-8-yloxy)-2,2-dimethylpropan-1-amine;-   2-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((cis)-3-fluoropiperidin-4-yloxy)quinoline;-   cis-2-(7-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-3-fluoropiperidin-4-yloxy)quinoline;

(S)-2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(pyrrolidin-2-ylmethoxy)quinoline;

-   3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)propane-1,2-diol;-   3-(2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethylpropan-1-amine;-   3-(2-(6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethylpropan-1-amine;-   2,2-Dimethyl-3-(2-(6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)propan-1-amine;-   2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-fluoropiperidin-4-yl)methoxy)quinoline;-   2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-methylpiperidin-4-yl)methoxy)quinoline;-   2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-ethylpiperidin-4-yl)methoxy)quinoline;-   2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-(cyclopropylmethyl)piperidin-4-yl)methoxy)quinoline;-   2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-isopropylpiperidin-4-yl)methoxy)quinoline;-   4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-1-benzylpiperidin-4-ol;-   4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)piperidin-4-ol;-   2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-methoxypiperidin-4-yl)methoxy)quinoline;-   2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(pyridin-4-yloxy)quinoline;-   4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)pyridin-2-amine;-   4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)pyrimidin-2-amine;-   2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-fluoropiperidin-4-yl)methoxy)-quinoline;-   2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((cis)-3-fluoropiperidin-4-yloxy)quinoline;-   2-(6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-fluoropiperidin-4-yl)methoxy)quinoline;-   2-(6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((cis)-3-fluoropiperidin-4-yloxy)quinoline;-   8-((4-fluoropiperidin-4-yl)methoxy)-2-(6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline;-   8-((cis)-3-fluoropiperidin-4-yloxy)-2-(6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline;-   2-(4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-4-fluoropiperidin-1-yl)acetamide;-   2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-fluoro-1-methylpiperidin-4-yl)methoxy)quinoline;-   2-(4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-4-fluoropiperidin-1-yl)ethanol;-   2-(4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-4-fluoropiperidin-1-yl)ethanol;-   (2S,4S)-methyl    4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)pyrrolidine-2-carboxylate;-   2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro-8-((cis)-3-fluoropiperidin-4-yloxy)quinoline;-   (S)-2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro-8-(piperidin-3-ylmethoxy)quinoline;-   Enantiomer 1 of    cis-2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro-8-5-fluoroazepan-4-yloxy)quinoline;-   Enantiomer 2 of    trans-2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro-8-5-fluoroazepan-4-yloxy)quinoline;-   Enantiomer 1 of    cis-8-5-fluoroazepan-4-yloxy)-2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline;-   2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(3,3-difluoropiperidin-4-yloxy)-6-fluoroquinoline;-   Enantiomer 1 of    2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((cis)-3-fluoropiperidin-4-yloxy)quinoline;-   Enantiomer 2 of    2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((cis)-3-fluoropiperidin-4-yloxy)quinoline;-   Enantiomer 1 of    2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((trans)-3-fluoropiperidin-4-yloxy)quinoline;-   Enantiomer 2 of    2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((trans)-3-fluoropiperidin-4-yloxy)quinoline;-   2-(6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((trans)-5-fluoroazepan-4-yloxy)quinoline;-   Enantiomer 1 of    8-((trans)-5-fluoroazepan-4-yloxy)-2-(6-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline;-   Enantiomer 2 of    8-((trans)-5-fluoroazepan-4-yloxy)-2-(6-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline;-   3-(8-((trans)-5-fluoroazepan-4-yloxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile;-   2-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((trans)-5-fluoroazepan-4-yloxy)quinoline;-   2-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-fluoropiperidin-4-yl)methoxy)quinoline;-   2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-84(1-ethyl-4-fluoropiperidin-4-yl)methoxy)quinoline;-   2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-84(4-fluoro-1-(2-fluoroethyl)piperidin-4-yl)methoxy)quinoline;-   2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro-8-((4-fluoropiperidin-4-yl)methoxy)quinoline;-   2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((3-fluoroazetidin-3-yl)methoxy)quinoline;-   2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro-8-((3-fluoroazetidin-3-yl)methoxy)quinoline;-   8-((4-fluoropiperidin-4-yl)methoxy)-2-(6-methoxy-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline;-   6-fluoro-8-((4-fluoropiperidin-4-yl)methoxy)-2-(6-methoxy-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline;-   8-((4-fluoropiperidin-4-yl)methoxy)-2-(7-(2-methoxyethoxy)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline;-   (R)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yloxy)-3,3-dimethylbutane-1,2-diol;-   (R)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-3,3-dimethylbutane-1,2-diol;-   2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro-8-((4-methoxyazepan-4-yl)methoxy)quinoline;-   2-(4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yloxy)methyl)-4-methoxyazepan-1-yl)ethanol;-   4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)azepan-4-ol;-   2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-methoxyazepan-4-yl)methoxy)quinoline;-   Stereoisomer 1 of    2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((trans)-5-fluoro-1-methylazepan-4-yloxy)quinoline;-   Stereoisomer 2 of    2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((trans)-5-fluoro-1-methylazepan-4-yloxy)quinoline;-   Stereoisomer 3 of    2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((trans)-5-fluoro-1-methylazepan-4-yloxy)quinoline;-   Stereoisomer 4 of    2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((trans)-5-fluoro-1-methylazepan-4-yloxy)quinoline;-   Enantiomer 2 of    2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro-8-((cis)-5-fluoroazepan-4-yloxy)quinoline;-   2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro-8-(trans-5-fluoroazepan-4-yloxy)quinoline;-   8-((cis-4,5)-5-fluoroazepan-4-yloxy)-2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline;-   2,2-dimethyl-3-(2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)propan-1-amine;-   2-(7-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((3R,4S)-3-fluoropiperidin-4-yloxy)quinoline;-   8-((4-methoxypiperidin-4-yl)methoxy)-2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline;-   2-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)morpholine;-   Enantiomer 1 of    2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(azepan-4-yloxy)quinoline;-   Enantiomer 2 of    2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(azepan-4-yloxy)quinoline;-   (1-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)cyclopentyl)methanamine;-   2-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)butan-1-ol;-   2-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-2-ethylbutan-1-ol;-   4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-3,3-dimethylbutan-1-amine;-   2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((3-fluoropiperidin-3-yl)methoxy)quinoline;-   N-(3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethylpropyl)-2-fluoroacetamide;-   3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-N-(2,2-difluoroethyl)-2,2-dimethylpropan-1-amine;-   3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethyl-N-(2,2,2-trifluoroethyl)propan-1-amine;    and

pharmaceutically acceptable salts thereof. Particular mention is made ofhydrochloride salts (including dihydrochloride and trihydrochloridesalts) and trifluoroacetate salts (including bis-trifluoroacetate salts)of the aforementioned compounds.

EXAMPLES

The following examples illustrate the invention. In the examplesdescribed below, unless otherwise indicated all temperatures are setforth in degrees Celsius. Reagents were purchased from commercialsuppliers such as Aldrich Chemical Company, Lancaster, TCI or Maybridge,and were used without further purification unless otherwise indicated.Tetrahydrofuran (THF), dichloromethane (DCM, methylene chloride),toluene, and dioxane were purchased from Aldrich in Sure seal bottlesand used as received.

The reactions set forth below were done generally under a positivepressure of nitrogen or argon or with a drying tube (unless otherwisestated) in anhydrous solvents, and the reaction flasks were typicallyfitted with rubber septa for the introduction of substrates and reagentsby syringe. Glassware was oven dried and/or heat dried.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the amount of ex vivo proliferation in response to theindicated HEL protein concentrations in cells harvested from micefollowing in vivo priming with HEL protein and 7 days of treatment withthe compound of Example 26 (circles) or vehicle control animals(squares).

FIG. 2 shows the amount of ex vivo IFNγ production in response to theindicated HEL protein concentrations in cells harvested from micefollowing in vivo priming with HEL protein and 7 days of treatment withthe compound of Example 26 (circles) or vehicle control (squares).

FIG. 3 shows the levels of HEL antigen-specific IgG, IgG1, IgG2a, IgG2b,and IgG3 antibodies present in mouse serum relative to vehicle control(defined as 100%) following 2 immunizations with protein antigen and 21days of in vivo treatment with the compound of Example 26.

FIG. 4 shows the mean clinical score over time in experimentalautoimmune encephalomyelitis (EAE) disease-induced in mice by adoptivetransfer of encephalogenic cells in the absence of further treatment(open squares), in vehicle-treated animals from day 0 to day 26 (soliddiamonds), and in animals treated with the compound of Example 26administered from day 0 to day 26 (open triangles).

FIG. 5 shows the mean clinical EAE disease score versus days postMOG(33-55) peptide immunization for mice treated from day 7 to day 27with vehicle (solid diamonds) or the compound of Example 26 (opentriangles) and for untreated animals (open squares).

FIG. 6 shows the histological score for inflammation (solid bars), glandloss (hatched bars) and erosion (bricked bars) in the colon of normalmice or mice following 21 days of treatment with vehicle or the compoundof Example 26 compared to normal mice as indicated in the murineCD4+CD45RBhi adoptive transfer model of inflammatory bowel disease.

FIG. 7 shows the histological score for mucosal thickening in a murineCD4+CD45RBhi adoptive transfer model of inflammatory bowel diseasefollowing 21 days of treatment with vehicle (solid bar) or the compoundof Example 26 (hatched bar) compared to normal animals (diamond-speckledbars).

FIG. 8 shows the titer of anti-dsDNA auto-antibodies in serum of miceafter 79 days of treatment with vehicle (solid black bars) or with thecompound of Example 26 (hatched bars) in the MRL/lpr model of lupusversus the titer in normal mice (speckled bar).

FIG. 9 shows the scored levels of proteinuria present in mice over thetime course of the experiment in the MRL/lpr model of lupus aftertreatment with vehicle (filled diamonds) or the compound of Example 26(open triangles), relative to normal animals (open squares).

Example A PIM-1 Enzyme Assay

The assay for the determination of PIM activity is based on theincorporation of [³³P]PO₄ from [γ-³³P]ATP into PIM2tide substrate andcapture of the radiolabeled peptide onto a Whatman P81(phosphocellulose) filter plate. The amount of radiolabeled product isthen measured by liquid scintillation counting. The final bufferconditions were as follows: 20 mM K⁺MOPS, pH 7.4, 10 mM MgCl₂, 0.005%Tween-20, 1 mM DTT. Assay mixtures contained 35 μM [γ-³³P]ATP (20μCi/mL), 7.5 μM PIM2tide and 0.25 nM PIM-1 in a total volume of 50 pt.Incubations were carried out for 60 min at 22° C. and quenched with 75μL of 200 mM H₃PO₄, filtered through a Whatman P81 plate and washed(1×200 μL and 5×100 μL ) with 200 mM H₃PO₄. Liquid scintillationcocktail (50 μL ) was then added per well, and the plate was counted for30 s/well using a TopCount NXT.

IC₅₀ Determinations

Compounds were prepared at 50× the final concentration in DMSO byconducting 3-fold serial dilutions from a 500-μM intermediate dilutionto give a 10-point dosing curve having a high dose of 10 μM. One-μLaliquots of these were then transferred to the assay mixtures above togive a final concentration of DMSO of 2%. A standard or referencecompound was typically included on each assay plate to validate thatplate. For each plate, percent of control (POC) values were calculatedfor each well. IC₅₀'s were estimated from the POC's using a standard4-parameter logistic model. The IC₅₀ is defined as the concentration ofinhibitor at which the POC equals 50 for the fitted curve. Compounds ofFormula I were found to have an average IC₅₀ below 10 μM when tested inthis assay. Specific IC₅₀ values are provided in Table 2.

Example B PIM-2 Enzyme Assay

Assay was performed as described in Example A, using 4 μM [γ-³³P]ATP (20μCi/mL), 1.0 μM PIM2tide and 1.5 nM GST-tagged recombinant full-lengthhuman PIM-2 in place of PIM-1. Compounds of Formula I were found to havean average IC₅₀ below 10 μM when tested in this assay. Specific IC₅₀values are provided in Table 2.

Example C PIM-3 Enzyme Assay

Assay was performed as described in Example A, using 30 μM [γ-³³P]ATP(20 μCi/mL), 3.75 μM PIM2tide and 0.5 nM recombinant rat PIM-3 in placeof PIM-1. Compounds of Formula I were found to have an average IC₅₀below 10 μM when tested in this assay. Specific IC₅₀ values are providedin Table 2.

Example D Cellular Proliferation Assay

The assay for determination of the antiproliferative activity ofmultiple Pim inhibitors in the JAK2-driven cell lines was conducted asfollows. Cells were plated out to 96-well plates at an initial densityof 10,000 cells/well in 95 pt. Compounds were prepared at 20× the finalconcentration in DMSO by conducting 3-fold serial dilutions to give a10-point dosing curve having a high dose of 1000 μM. Aliquots (5 μt) ofthese dilutions were then transferred to the appropriate wells of the96-well plates containing cells to yield a final DMSO concentration of0.5%. The cells were then incubated with compound for 72 hours at 37°C., 5% CO₂. CelltiterBlue reagent (Promega, Catalog #: G8080) was thenadded (20 μL/well) and incubated at 37° C., 5% CO₂ for 1-8 hoursdepending on the cell line being analyzed. The plate was then quantifiedemploying a fluorescence plate reader (Model: Gemini [MolecularDevices]; Settings: 560 nm (Ex)/590 nm (Em) 570 nm (cut-off) [CellTiterBlue Assay].

The values for each well were then converted to a percent of untreatedcontrol (POC). These POC values were then plotted as a function ofcompound concentration. A 4-parameter curve-fit analysis was performedfor each compound dilution and an IC₅₀ value was calculated from thiscurve.

Table 1 provides IC₅₀ values for certain compound of this invention whentested in this assay cell lines A-E listed below (Note: all arecommercially available from ATCC®).

Cell lines

A: PC3 (Androgen independent prostate cancer)

B: K562 (Ph+chronic myelogenous leukemia)

C: MV4-11 (Acute myelogenous leukemia)

D: BxPC3 (Pancreatic Cancer)

E: HepG2 (Hepatocellular Carcinoma)

F: BaF3 (Mouse pro-B-cell line)

G: BaF3 TEL-JAK2 (Mouse pro-B-cell transformed with TEL-JAK2 fusion)

H: BaF2 BCR-Ab1 (Mouse pro-B-cell transformed with BCR-Ab1 fusion)

The symbols in Table 1 are relative indicators of the inherent potencies(antiproliferative effect) of compounds of Examples 1, 16, 17, 18 and 26against multiple cell lines, tested according to the generalexperimental procedure outlined in Example D. The definitions of thesymbols are as follows:

ND data not determined

(−) IC₅₀ is >10 uM (+) IC₅₀ is <10 uM (++) IC₅₀ is <5 uM (+++) IC₅₀ is<2 uM

TABLE 1 Cell Line Example # A B C D E F G H 1 + − ND ND ND +++ +++ + 16++ + ND − − +++ +++ ++ 17 +++ + ND + + +++ +++ +++ 18 +++ ++ +++ + + ++++++ +++ 26 ++ + +++ ND ND +++ +++ +++

Table 2 provides IC₅₀ values for compounds of the invention when testedin the assays of Examples A, B and/or C.

TABLE 2 Example PIM-1 PIM-2 PIM-3 No. IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM)  11.6 1107 4.4  2 95 10000 448  3 3 807 25  4 22 6025 105  5 5 2021 20  632 10000 155  7 5 1045 35  8 16 5573 93  9 4 570 17 10 3 514 13 11 232470 33 12 30 4910 77 13 ND 189 9 14 2 562 11 15 16 4219 102 16 1 169 417 0.65 134 3 18 1.5 49 2 19 0.70 17 2 20 2 51 5 21 4 1354 ND 22 5 50125 23 2 144 6 24 0.8 77 4 25 4 686 20 26 3 137 9 27 3 323 13 28 2 143 429 5 585 30 30 3 318 13 31 4 413 19 32 4 399 17 33 5 279 19 34 13 134651 35 10 1359 48 36 ND ND ND 37 ND ND ND 38 ND ND ND 39 0.55 26 ND 40 121277 46 41 4 182 ND 42 0.75 22 ND 43 139 10000 ND 44 63 7473 ND 45 26.91734 ND 46 1 96 ND 47 32 1174 41 48 0.70 147 4 49 0.92 100 2 50 12 290 851 3 406 10 52 2 110 4 53 NA NA NA 54 178 10000 465 55 70 10000 222 56 9427 24 57 4 484 NA 58 10 204 NA 59 55 2866 98 60 26 1760 NA 61 132 10000728 62 34 1721 262 63 0.65 101 NA 64 0.64 323 5 65 0.8 174 NA 66 0.8 523 67 0.95 69 3 68 1.3 126 10 69 1.6 95 ND 70 0.75 67 ND 71 16 10000 11272 5.3 588 ND 73 0.96 79 5 74 151 1994 ND 75 263 8935 ND 76 648 10000 ND77 17 1389 ND 78 8 1278 ND 79 0.2 55 ND 80 2 1163 ND 81 0.45 142 ND 82 31035 ND 83 4 193 ND 84 2 73 ND 85 2 105 ND 86 3 142 10 87 167 ND 248 888 502 24 89 ND ND ND 90 0.4 131 2 91 0.8 39 0.9 92 1 244 3 93 4.4 506 ND94 19.4 1000 ND 95 9.8 481.8 ND 96 10.8 1000 ND 97 49 1000 ND 98 0.7661.3 ND 99 17.4 1000 39.7 100  1.5 351.9 2 101  13 1000 ND 102  4.9439.6 ND 103  1.4 65.6 ND 104  3.9 191.2 ND 105  8.7 409 ND 106  0.525.4 ND 107  9.4 1000 ND 108  7.3 489.2 ND 109  4.7 384.1 ND 110  1.9163.4 ND 111  8.3 1000 ND 112  3.3 299.9 10.1 113  2.2 166.9 8.8 114 0.7 86 ND 115  1.4 222.4 ND 116  11.8 1000 ND 117  1 91.5 ND 118  3 330ND 119  1.3 573.8 ND 120  11 958.6 10.9 Enantiomer 2 121  30.5 520.216.1 Enantiomer 1 122  17.5 1000 23.5 Enantiomer 2 123  0.9 156 ND 124 31 1000 ND 125  1 429.1 ND 126  14.2 353.7 ND 127  4.8 437.7 6.8 128 19.1 1000 79.4 129  4.9 1000 ND 130  5.8 1000 ND 131  2.3 1000 ND 132  176.5 ND 133  1.6 141.6 ND 134  10.1 951.8 ND 135  12.6 506.2 ND 136  5.5361.9 ND ND: Not determined

Example E T Cell In Vitro Functional Assays

The in vitro assays to assess the effects of the compounds of Examples16, 18 and 26 on T cells were conducted as described in assays A, B, Cand D below. CD4+T cells were isolated from red blood cell-depletedsplenocytes of C57B1/6J mice (Jackson Laboratories, catalog #000664)using CD4+T cell isolation kit (Miltenyi, catalog #130-090-860).

In assay (A), purified CD4+T cells were plated in 96 well plates at90000 cells/well in 90 μL. A dilution series of the compounds ofExamples 16, 18 and 26 were prepared at 100× the final concentration inDMSO and then diluted 10-fold into complete media (10× stocks). 10 μL of10×compound stocks were added to appropriate wells of 96 well platescontaining cells and incubated for 1 hour at 37° C., 5% CO₂. Thecell/compound mixtures were then transferred to a 96 well plate coatedwith anti-CD3 mAb (1 μg/mL; BD Pharmingen, catalog #553057) and solubleanti-CD28 mAb (1 μg/mL; BD Pharmingen, catalog #553294) was added.Plates were cultured at 37° C., 5% CO₂ for 40 hours. 20 μL of theculture were removed for determination of proliferation using theCellTitre-Glo™ luminescent assay (Promega, Catalog #G7571) according tothe manufacturer's protocol. The plate was quantified on a PackardTopCount instrument using luminescence protocol and data was analyzedusing Prism software.

In assay (B), purified CD4+cells were treated with compound andstimulated as described for assay (A). After 40 hours, supernatants wereassayed for IL-2 using R&D duo set ELISA kits (catalog #DY402). ELISAplates were quantified relative to a standard curve using MolecularDevices Versamax Reader at 450 nM and Softmax Pro software.

In assay (C), 1000000 cells/mL of purified CD4+T cells were mixed with 1μg/mL anti-CD28, 10 ng/mL IL-4 (R&D Systems cat #404-ML-010/CF) and 2μg/mL anti-IFNγ (R&D Systems cat #AB-485-NA) and placed into platescoated with 1 μg/mL anti-CD3. After 5 days, cells were harvested, washedand incubated overnight at 37° 5% CO₂. The following day, 50,000 cellswere plated into each well of a 96 well plate. A dilution series ofcompounds were prepared at 200× the final concentration in DMSO, then10×stocks were prepared by dilution in cell culture media. 10 μL of 10×stocks were added to the cells in the 96 well plate and incubated for 2hours at 37° C., 5% CO2. Cell/compound mixtures were then transferred towell coated with 0.1 μg anti-CD3 and incubated at 37° C., 5% CO₂.Culture supernatants were removed 18 hours later and tested for IL-4levels by ELISA (R&D Systems catalog #DY404). ELISA plates werequantified relative to a standard curve using Molecular Devices VersamaxReader at 450 nM and Softmax Pro software.

In assay (D), 1,000,000 cells/mL of purified CD4+T cells were mixed with1 μg/mL anti-CD28, 50 ng/mL IL-6 (R&D Systems cat #406-ML-025/CF), 1ng/mL TGFβ (R&D Systems cat #303-B2-002), 2 μg/mL anti-IL-4 (R&D Systemscat #AB-404-NA), 2 μg/mL anti-IFNγ (R&D Systems cat #AB-485-NA) andplaced into plates coated with 1 μg/mL anti-CD3. After 4 days, cellswere harvested, washed and 100,000 cells were plated into 96 well plate.A dilution series of compounds were prepared at 200× the finalconcentration in DMSO, then 10× stocks were prepared by dilution in cellculture media. 10 μL of 10× stocks were added to the cells in the 96well plate. After 2 hours, 50 ng IL-23 (R&D Systems catalog#1887-ML-010/CF) was added to each well and 18 hours later supernatantswere removed and tested for IL-22 levels by ELISA (R&D Systems catalog#M2200). ELISA plates were quantified relative to a standard curve usingMolecular Devices Versamax Reader at 450 nM and Softmax Pro software.

For each of assays A, B, C and D, the values for each well wereconverted to a percent of vehicle-treated (DMSO) control (POC). ThesePOC values were plotted as a function of compound concentration and anIC₅₀ calculated using a 4-parameter curve-fit analysis program. Table 3provides relative indicators of the inherent potencies of the compoundsof Examples 16, 18 and 26 in assays A, B, C and D.

TABLE 3 IL-4 IL-22 Compound of Proliferation IL-2 Production ProductionProduction Example # (Assay A) (Assay B) (Assay C) (Assay D) 16 +++ ++++++ +++ 18 +++ +++ +++ +++ 26 ++ ++ ++ ++ (−) IC₅₀ is ≧ 10 uM (+) IC₅₀is ≦ 10 uM (++) IC₅₀ is ≦ 5 uM (+++) IC₅₀ is ≦ 1 uM

The data shown in Table 3 indicate the compounds of Examples 16, 18 and26 decrease proliferation and cytokine production by T cells. These datasupport the utility of compounds of Formula I in diseases associatedwith T cells or the soluble factors (including IL-2, IL-4, IL-22)secreted by these cells.

Example F T Cell In Vivo Functional Assay

To determine the effect of compounds of Formula I on T cell responses,the following experiment was conducted. On Day O, C57BL/6 (JacksonLaboratories #000664, 6-8 weeks of age) were immunized at the base ofthe tail with 100 μg of hen egg lysozyme (HEL; Sigma #L7773) withcomplete Freund's adjuvant (CFA; Sigma #F5881). Starting on Day 0 andcontinuing until Day 7, mice were dosed twice a day by oraladministration with vehicle (water) or the compound of Example 26 (200mg/kg). On Day 7, opopiteal lymph nodes were removed, single cellsuspensions were prepared and 500,000 cells in 200 μL were activated in96 well plates with the indicated dose of HEL peptide. Followingincubation for 72 hours at 37° C., 5% CO₂, supernatants were harvestedfor IFNγ ELISA (R&D Systems catalog #MIF00) and proliferation wasassessed using the CellTitre-Glo™ luminescent assay (Promega, Catalog#G7571) with both assays performed according to the manufacturer'sprotocol. ELISA plates were quantified relative to a standard curveusing Molecular Devices Versamax Reader at 450 nM and Softmax Prosoftware; proliferation was quantitated on a Packard TopCount instrumentusing luminescence protocol and data was analyzed using excel software.

FIG. 1 shows the ex vivo HEL-specific proliferation following 7 days ofin vivo treatment with vehicle (squares) or the compound of Example 26(circles). FIG. 2 shows amount of IFNγ production following 7 days of invivo treatment with vehicle (squares) or the compound of Example 26(circles). Both HEL-specific proliferation and IFNγ production aredecreased relative to vehicle following dosing with a compound ofFormula I.

The data shown in FIGS. 1 and 2 demonstrate that immunization in thepresence of a compound of Formula I impairs the ability to generate a Tcell-mediated immune response, and support the utility of compounds ofFormula I in treating diseases associated with the immune system.

Example G B Cell In Vivo Functional Assay

To determine the effect of a compound of Formula I on B cell responses,the following experiment was conducted. On Day O, C57BL/6J mice (JacksonLaboratories #000664, 6-8 weeks of age) were immunized at the base ofthe tail with 20 μg of hen egg lysozyme (HEL; Sigma #L7773) withcomplete Freund's adjuvant (CFA; Sigma #F5881). Mice were re-immunizedon day 7 with 20 μg HEL in alum (Pierce catalog #77161). Starting on Day0 and continuing through Day 28, mice were dosed once a day by oraladministration with vehicle (water) or the compound of Example 26 (200mg/kg). Serum was collected on days 0, 7, 14, 21, and 28 and analyzedfor HEL-specific total IgG, IgG1, IgG2a, IgG2b, and IgG3 antibodyproduction by capture ELISA (antibodies purchased from Invitrogen,catalog #M30007, #M32107, #M32307, #M32507, #M32607). ELISA plates werequantitated using Molecular Devices Versamax reader at 450 nM. The groupmean titer of each antibody analyte was converted to percent of vehiclecontrol (=100%).

FIG. 3 shows the percent of vehicle control of HEL-specific total IgG,IgG1, IgG2a, IgG2b, and IgG3 antibodies on Day 21. Mice treated with thecompound of Example 26 (hatched bars) have decreased titers of IgG2a,IgG2b and IgG3.

These data demonstrate that a compound of Formula I can alter the natureof the B-cell antibody response resulting in a different profile ofantibody isotypes being produced. Isotypes of antibodies havedifferential functions. These data therefore support the utility ofcompounds of Formula I in treating diseases associated with B cells andcharacterized by pathogenic antibodies.

Example H Adoptive Transfer Experimental Autoimmune Encephalomyelitis

Having observed that compounds of Formula I inhibit T cell activation invitro and in vivo, the effect of a compound of Formula I on anautoimmune disease induced by T cells was determined using an adoptivetransfer EAE model, an animal model of human multiple sclerosis (Brain(2006), 129, 1953-1971). This model relies on the injection of T cellsfrom animals with EAE into disease-free host animals. This injection ofcells is known to those skilled in the art as adoptive transfer. Byinjecting the animals with activated, encephalogenic T cells, this modelis focused on the pathogenic stage of EAE autoimmune disease. On Day-14,C57BL/6 mice (Taconic Farms; 10 weeks old) were immunized with adisease-causing protein, MOG(35-55) peptide in complete Freund'sadjuvant (Hooke Laboratories, catalog #EK-0113). On Day -3, spleens wereharvested, single cell suspensions were prepared and then 5,000,000cells/mL were stimulated with 20 μg/mL MOG(33-55) peptide (OpenBiosystems), 30 ng/mL IL-12 (R&D Systems catalog #419-ML-010), 10 μg/mLanti-IFNγ antibody (BD Biosciences catalog #554408) at 37° C., 5% CO₂.On Day 0, 1,500,000 of these cells were injected intravenously into thetail veins of C57BL/6 recipient mice. The recipient mice were dividedinto treatment groups for vehicle (distilled water; 10 mL/kg) or thecompound of Example 26 (200 mg/kg), both administered by oral gavagetwice daily for 26 days. The recipient mice were scored daily days 0through 26 using the following clinical scoring system:

0.0—no symptoms

1.0—limp tail

2.0—limp tail and weakness of hind legs

3.0—limp tail and complete hind limb paralysis, or partial front andhind limb paralysis, or severe head tilting combined with pushingagainst cage wall and spinning when picked up by tail

4.0—limp tail, complete hind limb paralysis and partial front limbparalysis

5.0—Full body paralysis, or spontaneous rolling or found dead due toparalysis

FIG. 4 shows the group mean+/−SEM (standard error of the mean) ofclinical score for the duration of the adoptive transfer experiment forthe vehicle-treated animals (solid diamonds) and animals treated withthe compound of Example 26 (open triangles), relative to untreatedanimals (open squares). As shown, treatment with the compound of Example26 resulted in significant delay in disease onset in this model (where“disease onset” is defined by the first of 2 consecutive days with aclinical score greater than or equal to 1). Median day of onset of theuntreated and vehicle groups was day 6 while treatment with the compoundof Example 26 extended the median day of onset to 11 days. These resultssupport the utility of compounds of Formula I in the treatment ofmultiple sclerosis.

Example I MOG(35-55)-Induced Experimental Autoimmune Encephalomyelitis

To further determine the effect of compounds of Formula I on anautoimmune disease associated with T cells and cytokines, a MOG-inducedexperimental autoimmune encephalomyelitis (EAE) experiment wasperformed. MOG-induced EAE is an animal model of human multiplesclerosis (Brain (2006), 129, 1953-1971).

On Day 0, C57BL/6J mice (Jackson Laboratories #000664, 6-8 weeks of age)were injected subcutaneously with 100 μL of complete Freund's adjuvant(CFA) prepared as a 1:1 emulsion of (a) incomplete Freund's adjuvant(Difco, catalog #263910) containing 8 mg/mL m. tuberculosis H37RA(Difco, catalog #231141) and (b) phosphate buffered saline (PBS)containing 1 mg/mL MOG(35-55) peptide (California Peptide Research Inc).On the day 0 and 2, mice were injected intravenously with 200 ng ofpertussis toxin (List Biological Laboratories, catalog #181). On day 7,the mice were randomized into treatment groups which received vehicle(distilled water) or the compound of Example 26 (200 mg/kg) administeredby oral gavage twice daily from days 7 through 27.

The mice were scored daily on days 7 through 37 using the followingclinical scoring system:

0.0—no symptoms

0.5—tail weakness

1.0—limp tail

1.5—unsteady gait, mild hind limb ataxia

2.0—partial hind limb paralysis (hind limbs carrying weight)

2.5—partial hind limb paralysis (hind limbs not carrying weight)

3.0—full hind limb paralysis

3.5—full hind limb paralysis and partial front limb paralysis

4.0—full body paralysis

FIG. 5 shows daily clinical scores over time as mean+/−SEM for eachtreatment group. Vehicle-treated mice (filled diamonds) and untreatedmice (open squares) developed severe EAE, with median maximal scoresreaching 3.0 for both groups. Mice treated with the compound of Example26 (open triangles) had reduced paralysis with a median maximal score of1.5.

These results further demonstrate that treatment with a compound ofFormula I is efficacious in decreasing the severity of symptoms in EAE,and further support the utility of compounds of Formula I for thetreatment of diseases associated with pathogenic T cell responses,including multiple sclerosis.

Example J CD4+CD45RBhi Adoptive Transfer Inflammatory Bowel Disease

An adoptive transfer model of inflammatory bowel disease (IBD) wasperformed to determine the effect of compounds of Formula I on IBD,which is an autoimmune disease associated with T cells and cytokines

On Day 0, CD4+ T cells were isolated from the spleens of femaleBalb/cAnNCrl mice (Charles River Laboratories; 12 weeks old) asdescribed in Example E. The resulting cells were labeled withfluorescent antibodies against CD4 and CD45 markers and were sorted byflow cytometry for CD4+CD45RBhi cells based on fluorescence. 400,000CD4+CD45RBhi cells were then injected intraperitoneally intoC.B17/Icr-Prkdc^(scid)/IcrIcoCrl mice (Charles River Laboratories straincode 236; 12 weeks old). This injection of cells is known to thoseskilled in the art as adoptive transfer. On Day 21, mice were randomizedinto groups for oral gavage treatment with vehicle (1%carboxymethylcellulose sodium (CMC)/0.5% Tween 80 once daily; CMC, Sigmacatalog #C9481, Tween 80 Sigma catalog #P1754) or the compound ofExample 26 (200 mg/kg; twice daily). Treatments continued through Day42.

At the conclusion of the study, mice were sacrificed and the distal halfof their colons were placed in 10% neutral buffered formalin (RichardAllen Scientific catalog #53120-1) and paraffin embedded, sectioned into4 μm slices and stained with hematoxylin and eosin (H&E) for analysis bya board certified veterinary pathologist.

For each H&E stained section, submucosal edema was quantitated bymeasuring the distance from the muscularis mucosa to the internal borderof the outer muscle layer in a non-tangential area thought to mostrepresentative the severity of this change. Mucosal thickness was alsomeasured in a non-tangential area of the section that best representedthe overall mucosal thickness. This parameter is indicative of glandelongation and mucosal hyperplasia. The extent of inflammation(macrophage, lymphocyte and polymorphonuclear leukocyte (PMN)infiltrate) was assigned severity scores according to the followingcriteria:

Normal=0

Minimal=1 (generally focal affecting 1-10% of mucosa or if diffuse thenminimal)

Mild=2 (generally focal affecting 11-25% of mucosa or if diffuse thenmild)

Moderate=3 (26-50% of mucosa affected with areas of gland loss replacedby inflammatory cell infiltrate, milder in remaining areas of mucosa)

Marked=4 (51-75% of mucosa affected with areas of gland loss replaced byinflammatory cell infiltrate, milder in remaining areas of mucosa)

Severe=5 (76-100% of mucosa affected with areas of gland loss replacedby inflammatory cell infiltrate, milder in remaining areas of mucosa)

The parameters reflecting epithelial cell loss/damage were scoredindividually using a % area involved scoring method:

None=0

1-10% of the mucosa affected=1

11-25% of the mucosa affected=2

26-50% of the mucosa affected=3

51-75% of the mucosa affected=4

76-100% of the mucosa affected=5

Parameters that were scored using % involvement included: colonglandular epithelial loss (this includes crypt epithelial as well asremaining gland epithelial loss), and colon erosion (this reflects lossof surface epithelium and generally is associated with mucosalhemorrhage (reflective of the bleeding seen clinically and at necropsy).

The three scored parameters (inflammation, glandular epithelial loss,and erosion) were ultimately summed to arrive at a sum of histopathologyscores, which indicates the overall damage and would have a maximumscore of 15.

FIG. 6 shows the group mean+/−SEM colon histopathology scores forinflammation (solid bars), gland loss (hatched bars) and erosion (brickbars) in mice that were untreated (left bars), or treated with vehicle(middle bars) or the compound of Example 26 (right bars) following 21days of treatment. Treatment with the compound of Example 26 resulted inreduced severity of disease as assessed by these histologic endpoints.FIG. 7 shows the group mean+/−SEM for histological assessment of colonmucosal thickness for untreated animals (diamond-speckled bars) and foranimals treated with vehicle (solid black bars) or the compound ofExample 26 (hatched bars). Treatment with the compound of Example 26resulted in an 84% decrease in mucosal thickening (a sign of tissueinjury), relative to vehicle treated animals.

These results show that treatment with a compound of Formula I isefficacious in decreasing the severity of colon damage in a model of IBDand support the utility of compounds of Formula I for treatment diseasesassociated with pathogenic T cell responses, including IBD.

Example K MRL/lpr Lupus Model

MRL/lpr is considered to be an animal model of systemic lupuserythematosus (SLE), an autoimmune disease (Cohen and Maldonado 2003,Current Protocols in Immunology Chapter 15, Unit 15.20). MRL/lpr micehave a defect in the apoptosis of activated lymphocytes and over timedevelop a spontaneous and severe lymphoproliferative disordercharacterized by enlarged lymphoid organs, auto-antibody production andkidney disease resulting in proteinuria. SLE patients also exhibitauto-antibodies, and some patients develop kidney disease. To determinethe effect of compounds of Formula I in this model of SLE, the followingexperiment was conducted.

MRL/MpJ-Fas<lpr>and age-matched MRL/MpJ control mice (JacksonLaboratories, catalog #000485 and #000486, respectively) were treatedonce daily with vehicle (1% CMC/0.5% Tween 80) or twice daily with thecompound of Example 26 (200 mg/kg) for 10 weeks. Body weights,lymphadenopathy and urine protein levels were monitored weekly. Urineprotein levels were determined with Bayer Albustix dipsticks (Bayercatalog #2191) and scored according to the following scale:

0=none detected

0.5=trace amounts

1=30 mg/dL

2=100 mg/dL

3=300 mg/dL

4=2000 mg/dL

Serum levels of anti-ds-DNA antibody were measured by ELISA (AlphaDiagnostic, catalog #5120) on Day 28 and upon study termination. ELISAplates were quantitated using a Molecular Devices Versamax plate readerat 450 nM and titers calculated relative using to a standard curve usinga 4-parameter curve fit with Softmax Pro software.

Treatment with the compound of Example 26 for 28 days resulted in a 74%decrease in serum anti-dsDNA relative to vehicle control animals (datanot shown). FIG. 8 shows the group mean+/−SEM of anti-dsDNA levels atthe termination of the study (79 days of dosing) for untreated animals(speckled bar) and animals treated with vehicle (solid black bar) or thecompound of Example 26 (hatched bar). Treatment with compound of Example26 resulted in a 99% decrease in serum anti-dsDNA antibodies relative tovehicle control animals.

FIG. 9 shows the group mean+/−SEM proteinuria over time for normalanimals (open squares) and animals treated with vehicle (filleddiamonds) or the compound of Example 26 (open triangles) anddemonstrates that treatment with the compound of Example 26 prevents thedevelopment of proteinuria relative to vehicle control.

The results shown in FIGS. 8 and 9 support the utility of compounds ofFormula I in treating some aspects of lupus.

PREPARATIVE EXAMPLES Example 1

2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-N-(piperidin-4-yl)quinolin-8-aminedi-trifloroacetate

Step A: Preparation of8-(tert-butyldimethylsilyloxy)quinoline-2-carbaldehyde: To a solution of8-hydroxyquinoline-2-carbaldehyde (15.0 g, 86.62 mmol) and imidazole(12.97 g, 190.6 mmol) in anhydrous CH₂Cl₂ (250 mL) at 0° C. was addedtert-butylchlorodimethylsilane (14.36 g, 95.28 mmol). The mixture wasallowed to warm slowly to ambient temperature over 16 hours and thenpartitioned between CH₂Cl₂ and water. The aqueous phase was extractedwith CH₂Cl₂ and the combined organic phases were washed successivelywith saturated NaHCO₃, water and brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel pad filtration eluting with hexanes followed by 19:1 ethylacetate/hexanes to provide 23.69 g (95%) of desired product as a darkyellow oil.

Step B: Preparation of(E/Z)-8-(tert-butyldimethylsilyloxy)-2-((2-(pyridin-2-yl)hydrazono)methyl)quinoline:A solution of 8-(tert-butyldimethylsilyloxy)quinoline-2-carbaldehyde(23.40 g, 81.41 mmol) and 2-hydrazinylpyridine (8.88 g, 81.41 mmol) inethanol (500 mL) was stirred at ambient temperature for 16 hours. Theresulting precipitate was filtered, washed with cold ethanol and driedin vacuo to provide 30.82 g (82%) of desired product as a beige-coloredsolid.

Step C: Preparation of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(tert-butyldimethylsilyloxy)quinoline:To a suspension of(E/Z)-8-(tert-butyldimethylsilyloxy)-2-((2-(pyridin-2-yl)hydrazono)methyl)quinoline(25.40 g, 67.10 mmol) in anhydrous CH₂Cl₂ (400 mL) was addediodosobenzene diacetate (23.77 g, 73.81 mmol). The mixture was stirredat ambient temperature for 64 hours after which the solution waspartitioned between CH₂Cl₂ and saturated Na₂S₂O₃. The aqueous phase wasextracted with CH₂Cl₂ and the combined organic phases were washed withbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was triturated with diethyl ether, filtered anddried in vacuo to provide 18.92 g (75%) of desired product as a beigepowder.

Step D: Preparation of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol: To a solution of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(tert-butyldimethylsilyloxy)quinoline (18.92 g, 50.25 mmol) in anhydrous THF (400 mL) at 0° C. wasadded tetrabutylammonium fluoride (75.4 mL, 1.0 M/THF, 75.4 mmol). Afterstirring for 1 hour at this temperature the mixture was partitionedbetween saturated NaHCO₃ and EtOAc. The aqueous phase was extracted withEtOAc and the combined organic phases were washed with brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas triturated with CH₂Cl₂, filtered and dried in vacuo to provide 11.91g (90%) of desired product as a beige solid.

Step E: Preparation of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yltrifluoromethanesulfonate: To a suspension of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol (0.485 g, 1.85 mmol)in a mixture of THF (5 mL) and DMF (2 mL) was added triethylamine (0.57mL, 4.07 mmol) followed by N-phenyltriflimide (0.727 g, 2.03 mmol). Themixture was stirred at ambient temperature for 16 hours then treatedwith water (50 mL). The resulting precipitate was filtered, washedsuccessively with water and ether and dried in vacuo to provide 0.569 g(78%) of desired product as a light grey solid.

Step F: Preparation of tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ylamino)piperidine-1-carboxylate:2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yltrifluoromethanesulfonate (0.100 g, 0.25 mmol), tert-butyl4-aminopiperidine-1-carboxylate (0.102 g, 0.51 mmol), Pd₂ dba₃ (0.023 g,0.025 mmol), BINAP (0.032 g, 0.05 mmol) and cesium carbonate (0.124 g,0.38 mmol) were combined in a capped vial and stirred at 100° C. for 16hours. The cooled mixture was filtered through GF paper and the filtratepartitioned between saturated NaHCO₃ and EtOAc. The aqueous phase wasextracted with EtOAc and the combined organic phases were washed withbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography(CH₂Cl₂ followed by 1% MeOH/CH₂Cl₂) to provide 0.107 g (95%) of desiredproduct as an orange foam.

Step G: Preparation of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-N-(piperidin-4-yl)quinolin-8-aminedi-trifloroacetate: To a solution of tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ylamino)piperidine-1-carboxylate(0.107 g, 0.241 mmol) in CH₂Cl₂ (4 mL) was added TFA (1 mL). Thesolution was stirred at ambient temperature for 1 hour then concentratedunder reduced pressure. The residue was triturated with ether, filteredand dried in vacuo to provide 0.110 g (80%) of desired product as thedi-TFA salt. MS ESI (+) m/z 345 (M+1) detected.

Example 2

2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)quinolinamine

Prepared as described in Example 1 using tert-butyl4-amino-2,2,6,6-tetramethylpiperidine-1-carboxylate in place oftert-butyl 4-aminopiperidine-1-carboxylate in step F. MS ESI (+) m/z 401(M+1) detected.

Example 3

(trans)-4-(2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)quinolin-8-ylamino)cyclohexanol

Prepared as described in Example 1 using trans-(1,4)-4-aminocyclohexanolin place of tert-butyl 4-aminopiperidine-1-carboxylate in step F. MSAPCI (+) m/z 360 (M+1) detected.

Example 4

(S)-2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-N-(pyrrolidin-3-yl)quinolin-8-amine

Prepared as described in Example 1 using (S)-tert-butyl3-aminopyrrolidine-1-carboxylate in place of tert-butyl4-aminopiperidine-1-carboxylate in step F. MS ESI (+) m/z 331 (M+1)detected.

Example 5

(R)-2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-N-(pyrrolidin-3-yl)quinolin-8-amine

Prepared as described in Example 1 using (R)-tert-butyl3-aminopyrrolidine-1-carboxylate in place of tert-butyl4-aminopiperidine-1-carboxylate in step F. MS ESI (+) m/z 331 (M+1)detected.

Example 6

tert-Butyl3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ylamino)propylcarbamate

Prepared as described in Example 1 using tert-butyl3-aminopropylcarbamate in place of tert-butyl4-aminopiperidine-1-carboxylate in step F. MS ESI (+) m/z 419 (M+1)detected.

Example 7

N1-(2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)quinolin-8-yl)propane-1,3-diamine

Prepared as described in Example 1 using tert-butyl3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ylamino)propylcarbamate(Example 6). MS ESI (+) m/z 319 (M+1) detected.

Example 8

N1-(2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)quinolin-8-yl)-N1-isopentylpropane-1,3-diamine

Prepared as described in Example 1 using tert-butyl3-(isopentylamino)propylcarbamate in place of tert-butyl4-aminopiperidine-1-carboxylate in step F. MS ESI (+) m/z 389 (M+1)detected.

Example 9

2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(piperidin-4-yloxy)quinolinedi-trifluoroacetate

Step A: Preparation of tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)piperidine-1-carboxylate:To a suspension of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol(prepared according to Example 1; 112 mg, 0.427 mmol) in anhydrous THF(5 mL) at ambient temperature were added tert-butyl4-hydroxypiperidine-1-carboxylate (95 mg, 0.47 mmol), PPh₃ (168 mg, 0.64mmol), and DEAD (101 μL, 0.64 mmol). The resulting yellow solution wasstirred for 72 hours and then partitioned between saturated NaHCO₃ andethyl acetate (20 mL). The phases were separated and the aqueous layerwas extracted with ethyl acetate. The combined organics were dried overNa₂SO₄, filtered and concentrated under reduced pressure to afford ayellow oil. The oil was purified by flash column chromatography usinggradient elution (CH₂Cl₂ to 1% MeOH/CH₂Cl₂) to provide the Boc-protectedproduct (90 mg, 47%) as a white foam.

Step B: Preparation of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(piperidin-4-yloxy)quinolinedi-trifluoroacetate: The product from Step A was dissolved in CH₂Cl₂ (4mL) and treated with TFA (1 mL). After stirring for 2 hours, thereaction mixture was concentrated to afford a yellow solid. This wastriturated with ether, filtered and dried in vacuo to afford the desiredproduct as the di-TFA salt, as a white solid. MS ESI (+) m/z 346 (M+1)detected.

Example 10

3-(2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)propan-1-amine

Prepared as described in Example 9 using tert-butyl3-hydroxypropylcarbamate in place of tert-butyl4-hydroxypiperidine-1-carboxylate in step A. MS ESI (+) m/z 320 (M+1)detected.

Example 11

(R)-2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-8-(pyrrolidin-3-yloxy)quinoline

Prepared as described in Example 9 using (S)-tert-butyl3-hydroxypyrrolidine-1-carboxylate in place of tert-butyl4-hydroxypiperidine-1-carboxylate in step A. MS ESI (+) m/z 332 (M+1)detected.

Example 12

(S)-2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-8-(pyrrolidin-3-yloxy)quinoline

Prepared as described in Example 9 using (R)-tert-butyl3-hydroxypyrrolidine-1-carboxylate in place of tert-butyl4-hydroxypiperidine-1-carboxylate in step A. MS ESI (+) m/z 332 (M+1)detected.

Example 13

(2S,4S)-Methyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)piperidine-2-carboxylate

Prepared as described in Example 9 using (2S,4R)-1-tert-butyl 2-methyl4-hydroxypiperidine-1,2-dicarboxylate in place of tert-butyl4-hydroxypiperidine-1-carboxylate in step A. MS ESI (+) m/z 404 (M+1)detected.

Example 14

2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-8-(piperidin-4-ylmethoxy)quinoline

Prepared as described in Example 9 using tert-butyl4-(hydroxymethyl)piperidine-1-carboxylate in place of tert-butyl4-hydroxypiperidine-1-carboxylate in step A. MS ESI (+) m/z 360 (M+1)detected.

Example 15

2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-8-(2-(piperidin-2-yl)ethoxy)quinoline

Prepared as described in Example 9 using tert-butyl2-2-(hydroxyethyl)piperidine-1-carboxylate in place of tert-butyl4-hydroxypiperidine-1-carboxylate in step A. MS ESI (+) m/z 374 (M+1)detected.

Example 16

2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-8-(piperidin-3-ylmethoxy)quinoline

Prepared as described in Example 9 using tert-butyl3-(hydroxymethyl)piperidine-1-carboxylate in place of tert-butyl4-hydroxypiperidine-1-carboxylate in step A. MS ESI (+) m/z 360 (M+1)detected.

Example 17

(trans)-4-(2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)cyclohexanamine

Prepared as described in Example 9 usingcis-tert-butyl-(1,4)-4-hydroxycyclohexylcarbamate in place of tert-butyl4-hydroxypiperidine-1-carboxylate in step A. MS ESI (+) m/z 360 (M+1)detected.

Example 18

3-(2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethylpropan-1-amine

Prepared as described in Example 9 using tert-butyl3-hydroxy-2,2-dimethylpropylcarbamate as a replacement for tert-butyl4-hydroxypiperidine-1-carboxylate in step A. MS ESI (+) m/z 348 (M+1)detected.

Example 19

3-(2-(7-(aminomethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethylpropan-1-ol

Step A: Preparation of8-(tert-butyldimethylsilyloxy)-2-((E)-((Z)-(4-iodopyridin-2(1H)-ylidene)hydrazono)methyl)quinoline:To 8-(tert-butyldimethylsilyloxy)quinoline-2-carbaldehyde (3.21 g, 11.2mmol) in DCM (30 mL) was added(Z)-1-(4-iodopyridin-2(1H)-ylidene)hydrazine (3.15 g, 13.4 mmol). Thereaction was stirred for 1 hour, affording a yellow precipitate, whichwas collected by filtration and used without further purification in thenext step.

Step B: Preparation of8-(tert-butyldimethylsilyloxy)-2-(7-iodo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline:8-(tert-butyldimethylsilyloxy)-2-((E)-((Z)-(4-iodopyridin-2(1H)-ylidene)hydrazono)methyl)quinolinewas weighed into a 1 neck flask and dissolved in THF. Iodobenzenediacetate (IBD) (4.199 g) was added portionwise, and the reaction wasstirred for 5 minutes. The reaction was quenched with saturated Na₂S₂O₃(20 mL). The phases were separated, followed by extraction of theaqueous phase with DCM. The combined organics were dried over Na₂SO₄ andconcentrated in vacuo. The crude material was purified by flash columnchromatography (eluting with a 2:1 mixture of Hexanes/ethyl acetate),affording the desired product.

Step C: Preparation of8-(tert-butyldimethylsilyloxy)-2-(7-vinyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline:To8-(tert-butyldimethylsilyloxy)-2-(7-iodo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline(2.011 g, 4.003 mmol) in NMP/THF (10 mL/10 mL) was addedtributyl(vinyl)stannane (1.523 g, 4.803 mmol), trifuran-2-ylphosphine(0.0929 g, 0.400 mmol), Pd₂ dba₃ (0.367 g, 0.4003 mmol) andtriethylamine (0.405 g, 4.00 mmol). The reaction was degassed with N₂and heated to 60° C. for 1 hour. The crude mixture was diluted withethyl acetate and the organic layer was washed with H₂O. The combinedorganics fractions were dried over Na₂SO₄ and concentrated in vacuo. Thecrude material was purified by flash column chromatography (eluting witha 5:1 mixture of Hexanes/ethyl acetate), affording the desired product.

Step D: Preparation1-(3-(8-(tert-butyldimethylsilyloxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)ethane-1,2-diol:To8-(tert-butyldimethylsilyloxy)-2-(7-vinyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline(1.321 g, 3.281 mmol) in acetone (10 mL) was added NMO (0.577 g, 4.93mmol) and OsO₄ (0.5 mL, 3.28 mmol) (0.025% in tBuOH). The reaction wasstirred for 4 hours, quenched with saturated Na₂S₂O₃ and concentrated invacuo. DCM was added to the crude slurry, and the aqueous layer wasseparated. The organics were dried over Na₂SO₄ and concentrated toprovide the crude product.

Step E: Preparation of3-(8-(tert-butyldimethylsilyloxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde:Sodium periodate (6.060 mL, 3.939 mmol) was added to silica gel (6 g) inDCM (10 mL), affording a slurry.1-(3-(8-(tert-butyldimethylsilyloxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)ethane-1,2-diol(1.433 g, 3.282 mmol) in DCM (10 mL) was added to the slurry and thereaction was stirred for 1 hour. The silica gel was removed byfiltration and washed with DCM. The filtrate was concentrated in vacuoto provide the crude product.

Step F: Preparation of(3-(8-(tert-butyldimethylsilyloxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol:NaBH₄ (0.124 g, 3.28 mmol was added to a solution of3-(8-(tert-butyldimethylsilyloxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-7-carbaldehyde(1.328 g, 3.283 mmol) in MeOH (20 mL) at 0° C. The cold bath was removedand the reaction allowed to warm to ambient temperature over 1 hour. HClwas added and the solution was concentrated. The residue was trituratedwith DCM. The resulting solid was filtered and concentrated to providethe crude product.

Step G: Preparation of2-((3-(8-(tert-butyldimethylsilyloxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methyl)isoindoline-1,3-dione:DEAD (0.6524 mL, 4.143 mmol) was added to a solution of(3-(8-(tert-butyldimethylsilyloxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol(1.123 g, 2.762 mmol), isoindoline-1,3-dione (0.6096 g, 4.143 mmol) andtriphenylphosphine (1.087 g, 4.143 mmol) in THF (20 mL) at 0° C.Following addition, the cold bath was removed and the reaction stirredat ambient temperature for 3 hours. The crude reaction was concentratedand the residue was purified by flash column chromatography (elutingwith at 1:4 mixture of ethyl acetate/Hexanes) to afford the desiredproduct mixed with triphenylphosphine oxide.

Step H: Preparation of243-(8-hydroxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methyl)isoindoline-1,3-dione:To a solution of2-((3-(8-(tert-butyldimethylsilyloxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methyl)isoindoline-1,3-dione(1.012 g, 1.889 mmol) and silica gel (3 g) in THF (20 mL) was added TBAF(2.267 mL, 2.267 mmol) (1M in THF). The reaction was stirred for 20minutes, then filtered and washed with DCM/MeOH (10:1). The combinedorganics were concentrated in vacuo to afford the desired crude product.

Step I: Preparation of2-((3-(8-(3-hydroxy-2,2-dimethylpropoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methyl)isoindoline-1,3-dione:Cs₂CO₃ (0.513 g, 1.57 mmol) was added to a solution of2-43-(8-hydroxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methyl)isoindoline-1,3-dione(0.221 g, 0.524 mmol) and 3-bromo-2,2-dimethylpropan-1-ol (0.350 g, 2.10mmol) in DMA (2 mL). The reaction was sealed and heated at 100° C. andstirred for 30 minutes. The reaction was cooled to ambient temperatureand diluted with EtOAc/H₂O (2:1). The phases were separated and theaqueous layer was extracted with ethyl acetate. The combined organicswere dried over Na₂SO₄ and concentrated in vacuo. The crude material waspurified by flash column chromatography (eluting with a 20:1 mixture ofDCM/MeOH), to afford the desired product.

Step J: Preparation of3-(2-(7-(aminomethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethylpropan-1-ol:To a solution of2-43-(8-(3-hydroxy-2,2-dimethylpropoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methyl)isoindoline-1,3-dione(0.056 g, 0.11 mmol) in EtOH (2 mL) was added hydrazine (0.018 g, 0.55mmol), and the reaction was stirred for 30 minutes. The reaction wasconcentrated, and the crude material was purified by flash columnchromatography (eluting with a 20:1:0.1 mixture of DCM/MeOH/NH₄OH) toafford the desired product (4 mg). MS ESI (+) m/z 378 (M+1) detected.

Example 20

(3-(8-isobutoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanamine

Prepared as described in Example 19, using 2-methylpropan-1-ol in placeof 3-bromo-2,2-dimethylpropan-1-ol in step 1. MS ESI (+) m/z 348 (M+1)detected.

Example 21

3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-N,N,2,2-tetramethylpropan-1-amine

Prepared as described in Example 9, using3-(dimethylamino)-2,2-dimethylpropan-1-ol in place of tert-butyl4-hydroxypiperidine-1-carboxylate in step A. MS ESI (+) m/z 376.2 (M+1)detected.

Example 22

(1-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)cyclopropyl)methanol

Prepared as described in Example 9, using1,1-bis(hydroxymethyl)cyclopropane in place of tert-butyl4-hydroxypiperidine-1-carboxylate in step A. MS ESI (+) m/z 347.1 (M+1)detected.

Example 23

2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(neopentyloxy)quinoline

To a solution of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol(100 mg, 0.38 mmol), Example 1, Step D, in anhydrous DMA (2 mL) wasadded cesium carbonate (373 mg, 1.14 mmol) followed by neopentyl iodide(101 μL, 0.76 mmol). The heterogeneous mixture was stirred at ambienttemperature for 2 hours then at 100° C. for 16 hours. The cooled mixturewas treated with water (30 mL) and extracted with EtOAc (3×20 mL). Thecombined organic phases were washed with water and brine, dried overNa₂SO₄ and concentrated to afford a cream-colored solid. This wastriturated with ether and the resulting solid collected by filtrationand dried in vacuo to provide desired product (62 mg, 49%) as a whitepowder. MS ESI (+) m/z 333.3 (M+1) detected.

Example 24

3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethylpropan-1-ol

Prepared as described in Example 23 using3-bromo-2,2-dimethylpropan-1-ol in place of neopentyl iodide. MS ESI (+)m/z 349.2 (M+1) detected.

Example 25

2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((trans)-3-fluoropiperidin-4-yloxy)quinoline

Prepared as described in Example 23 using(cis)-tert-butyl-3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylatein place of neopentyl iodide. Boc deprotection was achieved as describedin Example 9, Step B. MS ESI (+) m/z 364.1 (M+1) detected.

Example 26

2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((cis)-3-fluoropiperidin-4-yloxy)quinolinedihydrochloride

Prepared as described in Example 23, using(trans)-tert-butyl-3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylatein place of(cis)-tert-butyl-3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylate.MS ESI (+) m/z 364.1 (M+1) detected.

A more detailed description of the synthesis is described in Steps A andB below.

Step A: Preparation of cis-(3,4)-tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-3-fluoropiperidine-1-carboxylate:2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol (5.1 g, 19 mmol),trans-(3,4)-tert-butyl3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylate (5.8 g, 19 mmol)and cesium carbonate (19 g, 58 mmol) were combined in a round bottomflask and dissolved in 120 mL of DMA and heated at 100° C. overnight,after which the reaction was complete by TLC. The reaction was filteredand the mother liquor concentrated in vacuo. The residue was purified byflash column chromatography, gradient elution 1-10% MeOH/DCM, affordingthe desired product as a yellow solid containing the starting marterial2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol as an impurity. MSESI (+) m/z 464.0 (M+1) detected.

Step B: Preparation of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(cis-(3,4)-3-fluoropiperidin-4-yloxy)quinolinedihydrochloride: cis-(3,4)-tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-3-fluoropiperidine-1-carboxylate(9.0 g, 19 mmol) was weighed into a round bottom flask and dissolved in300 mL of chloroform. HCl (49 mL, 194 mmol) was added dropwise, followedby stirring for 1 hour at ambient temperature, at which time thereaction was complete by LC/TLC. The crude product was collected byfiltration, wash with 3×100 mL of DCM and then Et₂O, affording thedesired product (4.7 g, 13 mmol, 67% yield) as an off white powder.

Example 27

3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-N-ethyl-2,2-dimethylpropan-1-aminedi-trifluoroacetate

Step A: Preparation of tert-butyl3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethylpropyl(ethyl)carbamate:To a solution of tert-butyl3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethylpropylcarbamate(50 mg, 0.11 mmol) in anhydrous DMF (2 mL) was added NaH (7 mg, 60%,0.17 mmol). After stirring at ambient temperature for 20 min, ethyliodide (27 μL, 0.34 mmol) was added and the mixture stirred for afurther 5 hrs. The mixture was treated with saturated NH₄Cl (20 mL) andextracted with EtOAc (3×10 mL). The combined organic phases were washedwith water and brine and concentrated to afford a yellow gum. Theresidue was purified by flash column chromatography using gradientelution (CH₂Cl₂ to 1% MeOH/CH₂Cl₂ to 2% MeOH/CH₂Cl₂) to afford desiredproduct (45 mg, 85%) as a colorless gum.

Step B: Preparation of3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-N-ethyl-2,2-dimethylpropan-1-aminedi-trifluoroacetate: To a solution of tert-butyl3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethylpropyl(ethyl)carbamate(45 mg, 0.09 mmol) in CH₂Cl₂ (4 mL) was added TFA (1 mL). Theyellow/brown solution was stirred at ambient temperature for 2 hoursthen concentrated and dried in vacuo. The residue was triturated withether, filtered and dried in vacuo to afford desired product (44 mg,76%) as the di-TFA salt as a white solid. MS APCI (+) m/z 376.2 (M+1)detected.

Example 28

3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-N,2,2-trimethylpropan-1-amine

Prepared as described in Example 27, using methyl iodide in place ofethyl iodide in Step A. MS APCI (+) m/z 362.2 (M+1) detected.

Example 29

8-(8-azabicyclo[3.2.1]octan-3-yloxy)-2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline

Prepared as described in Example 9, using tert-butyl3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate in place of tert-butyl4-hydroxypiperidine-1-carboxylate in step A. MS ESI (+) m/z 372.2 (M+1)detected.

Example 30

(2S)-3-(2([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2-ethylpentan-1-amine

Step A: Preparation of tert-butyl (2S)-3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2-ethylpentylcarbamate:2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol (101 mg, 0.385mmol), tert-butyl (2S )-2-ethyl-3-hydroxypentylcarbamate (89 mg, 0.385mmol), PPh₃ (151 mg, 0.577 mmol) and DEAD (90.9 μL, 0.577 mmol) werecombined at ambient temperature in 5 mL anhydrous THF. The reactionmixture was heated at reflux for 6 hours. The crude mixture was cooledto ambient temperature and diluted with water and ethyl acetate. Thecrude mixture was extracted with ethyl acetate, and the combined organiclayers were dried over Na₂SO₄ and concentrated in vacuo to provide thedesired product.

Step B: Preparation of(2S)-3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2-ethylpentan-1-amine:tert-Butyl(2S)-3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2-ethylpentylcarbamatewas dissolved in 5 mL DCM and cooled to 0° C. TFA (5 mL) was added andthe mixture was allowed to warm to ambient temperature over 1 hour. Thereaction mixture was evaporated to dryness, and the residue wasdissolved in 30 mL DCM and washed with 1N NaOH. The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated under vacuum.The residue was purified by silica gel chromatography followed bypreparative TLC to give the desired product (42.5 mg, 29%).

MS ESI (+) m/z 376.1 (M+1) detected.

Example 31

(2R)-3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2-ethylpentan-1-amine

Prepared as described in Example 30, using tert-butyl(2R)-2-ethyl-3-hydroxypentylcarbamate in place of tert-butyl (2S)-2-ethyl-3-hydroxypentylcarbamate in step A. MS ESI (+) m/z 376.1 (M+1)detected.

Example 32

(2S)-3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2-ethylbutan-1-amine

Prepared as described in Example 30, using tert-butyl (2S)-2-ethyl-3-hydroxybutylcarbamate in place of tert-butyl (2S)-2-ethyl-3-hydroxypentylcarbamate in step A. MS ESI (+) m/z 362.1 (M+1)detected.

Example 33

(2R)-3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2-ethylbutan-1-amine

Prepared as described in Example 30, using tert-butyl(2R)-2-ethyl-3-hydroxybutylcarbamate in place of tert-butyl (2S)-2-ethyl-3-hydroxypentylcarbamate in step A. MS ESI (+) m/z 362.2 (M+1)detected.

Example 34

(2S)-3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2-ethylhexan-1-amine

Prepared as described in Example 30, using tert-butyl(2S)-2-ethyl-3-hydroxyhexylcarbamate in place of tert-butyl(2S)-2-ethyl-3-hydroxypentylcarbamate in step A. MS ESI (+) m/z 390.2(M+1) detected.

Example 35

(2R)-3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2-ethylhexan-1-amine

Prepared as described in Example 30 using tert-butyl(2R)-2-ethyl-3-hydroxyhexylcarbamate in place of tert-butyl(2S)-2-ethyl-3-hydroxypentylcarbamate in step A. MS ESI (+) m/z 390.2(M+1) detected.

Example 36

(2S,4R)-methyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)pyrrolidine-2-carboxylate

Prepared as described in Example 13, using (2S,4S)-1-tert-butyl 2-methyl4-hydroxypyrrolidine-1,2-dicarboxylate in place (2S,4R)-1-tert-butyl2-methyl 4-hydroxypiperidine-1,2-dicarboxylate. MS ESI (+) m/z 390.2(M+1) detected.

Example 37

2-(7-(2-methoxyethoxy)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol

Step A: Preparation of 2-chloro-4-(2-methoxyethoxy)pyridine: Potassium2-methylpropan-2-olate (4.214 g, 35.68 mmol) was slowly added to asolution of 2-chloro-4-nitropyridine (5.142 g, 32.434 mmol) in2-methoxyethanol (40.0 mL, 506.74 mmol). The reaction was stirred atambient temperature for 2 hours, then concentrated under reducedpressure. The resulting oil was diluted with water (200 mL) andextracted with Ethyl acetate (2×100 mL). The combined organic phaseswere dried over Na₂SO₄, filtered and concentrated under reduced pressureto give 5.36 g (88%) of the desired product as a colorless oil.

Step B: Preparation of 2-hydrazinyl-4-(2-methoxyethoxy)pyridine:Hydrazine (10 mL, 318.6 mmol) was added to a solution of2-chloro-4-(2-methoxyethoxy)pyridine (1.00 g, 5.330 mmol) in pyridine(25 mL), then heated to reflux. After 18 hours the reaction mixture waspartitioned between H₂O and DCM and the aqueous phase was extracted withDCM. The combined organic extracts were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography (40:1 DCM/MeOH followed by 20:1 DCM/MeOH) toprovide 320 mg (33%) of desired product as a white solid.

Step C: Preparation of8-(tert-butyldimethylsilyloxy)quinoline-2-carbaldehyde:8-Hydroxyquinoline-2-carbaldehyde (5.00 g, 28.9 mmol) and imidazole(4.32 g, 63.5 mmol) were dissolved in DCM (50 mL) under N₂. The reactionmixture was cooled to 0° C., followed by addition oftert-butylchlorodimethylsilane (4.94 g, 31.8 mmol). After stirring for16 hours at ambient temperature the reaction mixture was partitionedbetween DCM and H₂O. The organic layer was washed with H₂O and aqueoussaturated NaHCO₃, dried over Na₂SO₄, filtered and concentrated underreduced pressure to afford an orange oil. The residue was purified byflash column chromatography (10:1 Hexanes/EtOAc) to provide 6.85 g (83%)of desired product as a yellow/orange oil.

Step D: Preparation of8-(tert-butyldimethylsilyloxy)-2-((2-(4-(2-methoxyethoxy)pyridin-2-yl)hydrazono)methyl)quinoline:2-Hydrazinyl-4-(2-methoxyethoxy)pyridine (0.076 g, 0.415 mmol) and8-(tert-butyldimethylsilyloxy) quinoline-2-carbaldehyde (0.119 g, 0.415mmol) were heated to reflux in EtOH (2 mL) for 16 hours. After coolingto ambient temperature the reaction mixture was filtered and washed withEtOH to provide 105 mg (56%) of desired product as an orange solid.

Step E: Preparation of8-(tert-butyldimethylsilyloxy)-2-(7-(2-methoxyethoxy)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline:To a solution of8-(tert-butyldimethylsilyloxy)-2-((2-(4-(2-methoxyethoxy)pyridin-2-yl)hydrazono)methyl)quinoline (0.101 g, 0.223 mmol) in DCM (1.0 mL) was added iodosobenzenediacetate (0.0719 g, 0.223 mmol). After stirring at ambient temperaturefor 5 hours the reaction mixture was partitioned between DCM and aqueoussaturated Na₂S₂O₃. The organic layer was washed with brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography (40:1 DCM/MeOH) to provide70 mg (70%) of desired product.

Step F: Preparation of2-(7-(2-methoxyethoxy)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol:To a solution of8-(tert-butyldimethylsilyloxy)-2-(7-(2-methoxyethoxy)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline(0.070 g, 0.155 mmol) in THF (8 mL) was added 1M HCl (1.5 mL, 1.50mmol). After stirring at ambient temperature for 2 hours, 1 M HCl (5 mL)was added and the reaction mixture stirred for an additional 16 hours.The mixture was neutralized with 1M NaOH and diluted with EtOAc. Theorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give 40 mg (77%) of desiredproduct. MS APCI (+) m/z 337.3 (M+1) detected.

Example 38

2-(7-methoxy-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol

Prepared as described in Example 37 using the 4-methoxy-2-chloropyridinein place of 2-chloro-4-(2-methoxyethoxy)pyridine. MS APCI (+) m/z 293.5(M+1) detected.

Example 39

3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yloxy)-2,2-dimethylpropan-1-amine

Step A: Preparation of 6-fluoro-2-methylquinolin-8-ol:2-amino-5-fluorophenol (13.0 g, 102 mmol) was dissolved in 6N HCl (78mL) and heated to reflux. The solution was treated with (E)-but-2-enal(8.8 mL, 107 mmol) in 1 mL portions over 1 hour. The reaction was heatedat reflux for 13 hours. The reaction mixture was cooled and adjusted topH 8 with concentrated NH₄OH. The reaction was diluted with ethylacetate, stirred for 30 minutes then filtered through a nylon membrane(0.45 μM). The filtrate was separated and the aqueous was washed withethyl acetate then the combined organics were washed with saturatedNaHCO₃, saturated NaCl, dried over Na₂SO₄ and concentrated in vacuo toprovide the product as a thick dark oil (19 g). MS APCI (+) m/z 178.1(M+1) detected.

Step B: Preparation of6-fluoro-2-methyl-8-(triisopropylsilyloxy)quinoline:6-fluoro-2-methylquinolin-8-ol (19.0 g, 107 mmol) was dissolved inmethylene chloride (300 mL) and treated with 1H-imidazole (10.9 g, 160mmol) and triisopropylsilyl trifluoromethanesulfonate (33.1 mL, 123mmol). The reaction was stirred at ambient temperature for 13 hours. Thereaction mixture was quenched with saturated NH₄Cl and separated. Theorganic layer was washed twice with saturated NH₄Cl, dried over Na₂SO₄and concentrated in vacuo to provide the desired product (35 g).

Step C: Preparation of6-fluoro-8-(triisopropylsilyloxy)quinoline-2-carbaldehyde:6-fluoro-2-methyl-8-(triisopropylsilyloxy)quinoline (1.76 g, 5.29 mmol)was dissolved in dioxane (58 mL) and water (0.49 mL). The reaction wastreated with selenium dioxide (0.76 g, 6.8 mmol) and the mixture washeated to reflux for 13 hours. The mixture was cooled and filteredthrough GF/F paper. The filtered solids were washed with Et₂O and allthe filtrates were concentrated in vacuo. The crude mixture waschromatographed on SiO₂ eluting with a gradient of 1-5% Et₂O/hexanes toprovide the desired product (0.515 g).

Step D: Preparation of6-fluoro-2((2-(pyridin-2-yl)hydrazono)methyl)-8-(triisopropylsilyloxy)quinoline:6-Fluoro-8-(triisopropylsilyloxy)quinoline-2-carbaldehyde (15.0 g, 43.2mmol) and 2-hydrazinylpyridine (4.71 g, 43.2 mmol) were combined in 100mL of anhydrous EtOH, and stirred at ambient temperature over night.Following over night stirring, the desired product was collected byfiltration (washing with cold EtOH), affording6-fluoro-2-((2-(pyridin-2-yl)hydrazono)methyl)-8-(triisopropylsilyloxy)quinoline(14.0 g, 31.9 mmol, 74% yield) as a yellow-white powder.

Step E: Preparation of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro-8-(triisopropylsilyloxy)quinoline:6-Fluoro-2-((2-(pyridin-2-yl)hydrazono)methyl)-8-(triisopropylsilyloxy)quinoline(10 g, 23 mmol) was weighed into a 1000 mL 1 neck round bottom flask,followed by addition of iodo benzene diacetate (8.1 g, 25 mmol) and 400mL of dichloromethane. The mixture was stirred at ambient temperaturefor 24 hours, at which time the reaction was complete. The crude mixturewas partitioned with Na₂S₂O₃, back extracted with DCM, and the combinedorganics were washed with brine and dried over sodium sulfate, thenconcentrated in vacuo. The crude product was the purified by flashcolumn chromatography (SP1 Biotage Horizon, 1-15% MeOH/DCM gradientelution), affording the desired product (9.4 g, 94% yield) as a whitepowder.

Step F: Preparation of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-ol:2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro-8-(triisopropylsilyloxy)quinoline(5.00 g, 11.5 mmol) was dissolved in 250 mL of anhydrous THF, followedby cooling to 0° C., then addition of TBAF (4.49 g, 17.2 mmol).Following 1 hour, the reaction was complete by TLC, and the crudereaction partitioned between water and ethyl acetate. The crude work-upwas then filtered through standard filter paper with ethyl acetate wash,affording the desired product2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-ol (2.8 g,9.99 mmol, 87% yield) as a white solid.

Step G: Preparation of:3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yloxy)-2,2-dimethylpropan-1-amine:The desired product was prepared as described in Example 25 using3-(tert-butoxycarbonylamino)-2,2-dimethylpropyl methanesulfonate inplace of(cis)-tert-butyl-3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylate,and 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-ol inplace of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol. MS ESI (+)m/z 366 (M+1) detected.

Example 40

4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)piperidine-1-carboxamide

To a solution of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(piperidin-4-yloxy)quinoline(prepared as described in Example 9, 46 mg, 0.133 mmol) in CH₂Cl₂ (5 mL)were added DIEA (116 μL, 0.67 mmol), DMAP (2 mg, 0.01 mmol), andTMS-isocyanate (104 μL, 0.67 mmol). The reaction mixture was stirred atambient temperature for 16 hours then partitioned between saturatedNaHCO₃ and CH₂Cl₂. The aqueous layer was extracted with CH₂Cl₂ and thecombined organic phases were washed with brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified by flash columnchromatography with gradient elution (CH₂Cl₂ to 1% MeOH/CH₂Cl₂ to 3%MeOH/CH₂Cl₂) to afford desired product (33 mg, 64%) as a colorlessglass. MS ESI (+) m/z 411.2 (M+Na⁺) detected.

Example 41

3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-difluoropropan-1-amine

Prepared as described in Example 23 using3-(tert-butoxycarbonylamino)-2,2-difluoropropyl methanesulfonate inplace of neopentyl iodide. Boc deprotection was achieved as described inExample 9, Step B. MS ESI (+) m/z 356.2 (M+1) detected.

Example 42

(cis)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)cyclohexanamine

Prepared as described in Example 9, using tert-butyl(trans)-4-hydroxycyclohexylcarbamate in place of tert-butyl4-hydroxypiperidine-1-carboxylate. MS ESI (+) m/z 360.5 (M+1) detected.

Example 43

3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-5-fluoroquinolin-8-yloxy)-2,2-dimethylpropan-1-amine

Prepared as described in Example 39 using2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-5-fluoroquinolin-8-ol (which wasprepared from 2-amino-4-fluorophenol in place of 2-amino-5-fluorophenolin Step A) as a replacement for,2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-ol. MS ESI (+)m/z 366.2 (M+1) detected.

Example 44

2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(pyridin-3-ylmethoxy)quinoline

Prepared as described in Example 23 using 3-(iodomethyl)pyridine inplace of neopentyl iodide and DMF in place of DMA. MS ESI (+) m/z 354.2(M+1) detected.

Example 45

2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(pyridin-4-ylmethoxy)quinoline

Prepared as described in Example 23 using 4-(bromomethyl)pyridine inplace of neopentyl iodide and DMF in place of DMA. MS ESI (+) m/z 354.1(M+1) detected.

Example 46

2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(5-fluoroazepan-4-yloxy)quinoline

Step A: Preparation of 1-tert-butyl 4-ethyl4-fluoro-5-oxoazepane-1,4-dicarboxylate: NaH (2.66 g, 105 mmol) wassuspended in THF (300 mL) and cooled to 0° C., and 1-tert-butyl 4-ethyl5-oxoazepane-1,4-dicarboxylate (30 g, 105 mmol) was added as THFsolution (550 mL) using an addition funnel over 30 minutes. The mixturewas stirred for 30 minutes and then diluted with DMF (200 mL).Selectfluor (41.0 g, 116 mmol) was added as a DMF solution (200 mL). Themixture was warmed to ambient temperature and stirred for 2 hours. Themixture was then concentrated to remove THF and diluted with 1N KHSO₄(300 mL), water (300 mL) and EtOAc (750 mL). The organic layer waswashed with brine (2×250 mL). The combined aqueous layers were washedwith EtOAc (200 mL) and this organic layer was washed with brine (200mL). The combined organic layers were then dried over Na₂SO₄, filteredand concentrated. The crude product was passed through a silica gel plug(1 kg, 20 to 40% EtOAc/hexanes) to provide 23.6 g (74%) of the productas a colorless oil.

Step B: Preparation of tert-butyl 4-fluoro-5-oxoazepane-1-carboxylate:To a 500 mL flask containing the product from Step A (23.5 g, 77.5 mmol)was added DMSO (160 mL) followed by H₂O (6.98 mL, 387 mmol) and thenLiCl (16.4 g, 387 mmol). The mixture was warmed to 125° C. and stirredfor 5 hours. The resulting dark mixture was then cooled to ambienttemperature and diluted with EtOAc (500 mL) and washed with a saturatedaqueous NaHCO₃:water (1:1, 3×250 mL). The combined aqueous phase waswashed with EtOAc (100 mL) and the combined organic phases were washedwith brine and dried over Na₂SO₄, filtered and concentrated. The crudeoil was purified by column chromatography (10 to 30% EtOAc/hexanes) toprovide 10.0 g (56%) of the desired product as a light golden oil.

Step C: Preparation of tert-butyl4-fluoro-5-hydroxyazepane-1-carboxylate: To a 50 mL flask containing theproduct from Step B (1.0 g, 4.32 mmol) was added MeOH (20 mL), and theresulting solution was cooled to 0° C. NaBH₄ (0.409 g, 10.8 mmol) wascarefully added and the mixture stirred at 0° C. for 3.0 hours. Themixture was concentrated to remove the solvent and the residue was takenup in EtOAc (50 mL) and a saturated aqueous NH₄Cl solution (20 mL) wasadded followed by water (20 mL). The layers were mixed and separated andthe aqueous phase extracted with EtOAc (2×20 mL). The combined organicextracts were washed with brine and dried over Na₂SO₄, then filtered andconcentrated. The crude product was purified by column chromatography(10% to 60% EtOAc/hexanes gradient) to provide 0.980 g (97%) of theproduct as a thick colorless oil that solidified to a white solid whilestanding overnight. The product contained of a mixture of cis and transisomers.

Step D: Preparation of tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-5-fluoroazepane-1-carboxylate:Prepared as described in Example 9 using the product of Step C in placeof tert-butyl 4-hydroxypiperidine-1-carboxylate in Step A andsubstituting THF:Toluene (1:1) for THF. MS ESI (+) m/z 478.1 (M+1)detected.

Step E: Preparation of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((5-fluoroazepan-4-yloxy)quinoline:To a solution of tert-butyl4-(2-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-5-fluoroazepane-1-carboxylate(0.157 g, 0.329 mmol) in CHCl₃ (3.2 mL) was added HCl (3.29 mL, 13.2mmol, 4.0 M in dioxane). The mixture was stirred at ambient temperaturefor 5 hours and was then filtered directly. The solid was washed withCH₂Cl₂ (5 mL) and Et₂O (5 mL) and carefully dried in vacuo to afford thedesired product as an off-white solid. The salt was purified directly bycolumn chromatography (10% MeOH/CH₂Cl₂ with 1% NH₃) to provide the freeamine product as an off-white solid. MS ESI (+) m/z 378.1 (M+1)detected.

Example 47

Stereoisomer #1 of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(-5-fluoroazepan-4-yloxy)quinolinedihydrochloride

Step A: Preparation of Stereoisomer #1 of tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-5-fluoroazepane-1-carboxylate:The racemic material from Example 46 (Step D) was purified by ChiralHPLC OJ-H 85% MeOH/15% EtOH, to provide the first eluting peak as asingle stereoisomer (99% ee, 99% de), designated stereoisomer #1.

Step B: Preparation of Stereoisomer #1 of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(-5-fluoroazepan-4-yloxy)quinolinedihydrochloride: To a 10 mL flask containing the product from Step A(0.138 g, 0.289 mmol) was added CHCl₃ (3.0 mL). To this stirringsolution was added HCl (2.89 mL, 11.6 mmol, in dioxane). The mixture wasstirred at ambient temperature for 3.0 hours and then filtered directlyand washed with CH₂Cl₂ and Et₂O and dried carefully in vacuo. Thisprovided 0.120 g (92%) of the desired product as an off-white solid. MSESI (+) m/z 378.1 (M+1) detected.

Example 48

Stereoisomer #2 of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(5-fluoroazepan-4-yloxy)quinolinedihydrochloride

Step A: Preparation of Stereoisomer #2 of tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-5-fluoroazepane-1-carboxylate:The racemic material from Example 46 (Step D) was purified by ChiralHPLC OJ-H 85% MeOH/15% EtOH, to provide the second eluting peak as asingle stereoisomer (99% ee, 99% de), designated as stereoisomer #2.

Step B: Preparation of Stereoisomer #2 of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(5-fluoroazepan-4-yloxy)quinolinedihydrochloride: Deprotection was performed as described in Example 47,step B. MS ESI (+) m/z 378.1 (M+1) detected. Specific rotation: [α]²⁵_(D)=−66° (c=0.5, MeOH).

Example 49

Stereoisomer #3 of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(5-fluoroazepan-4-yloxy)quinolinedihydrochloride

Step A: Preparation of Stereoisomer #3 of-tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-5-fluoroazepane-1-carboxylate:The racemic material from Example 46 (Step D) was purified by ChiralHPLC OJ-H 85% MeOH/15% EtOH, to provide the third eluting peak as asingle stereoisomer (99% ee, 99% de), designated as Stereoisomer #3.

Step B: Preparation of Stereoisomer #3 of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(5-fluoroazepan-4-yloxy)quinolinedihydrochloride: Deprotection was performed as described in Example 47,step B. MS ESI (+) m/z 378.1 (M+1) detected. Specific rotation: [α]²⁵_(D)=−71° (c=0.95, MeOH).

Example 50

Stereoisomer #4 of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(5-fluoroazepan-4-yloxy)quinolinedihydrochloride

Step A: Preparation of Stereoisomer #4 of tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-5-fluoroazepane-1-carboxylate:The racemic material from Example 46 (Step D) was purified by ChiralHPLC OJ-H 85% MeOH/15% EtOH, to provide the fourth eluting peak as asingle stereoisomer (99% ee, 60% de), designated as stereoisomer #4.

Step B: Preparation of Stereoisomer #4 of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(5-fluoroazepan-4-yloxy)quinolinedihydrochloride: Deprotection was performed as described in Example 47,step B. MS ESI (+) m/z 378.1 (M+1) detected.

Example 51

2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(3-fluoroazepan-4-yloxy)quinolinedihydrochloride

Step A: Preparation of 1-tert-butyl 4-ethyl6-fluoro-5-oxoazepane-1,4-dicarboxylate: A solution of tert-butyl3-fluoro-4-oxopiperidine-1-carboxylate (20.0 g, 92.1 mmol) in 1:1(CH₂Cl₂:Et₂O, 250 mL) was cooled to −60° C. using an IPA/dry ice bath.In a separate flask was added BF₃-Etherate (12.8 mL, 101 mmol) and Et₂O(40 mL) which was cooled to 0° C., then ethyl 2-diazoacetate (12.6 mL,120 mmol) was added. This mixture was added to the oxopiperidinesolution and the reaction mixture was slowly warmed to ambienttemperature over 2 hours. Water was added (100 mL) and the mixture wasstirred at ambient temperature for 30 minutes. The phases were separatedand the aqueous phase was extracted with EtOAc (100 mL) and the combinedorganic phases were washed with 1N KHSO₄, followed by brine and thendried over Na₂SO₄, filtered and concentrated. This provided the productas a thick, yellow oil (26 g).

Step B: Preparation of tert-butyl 3-fluoro-4-oxoazepane-1-carboxylate:The product from Step A was dissolved in DMSO (200 mL) and H₂O (8.29 g,460 mmol) followed by addition of LiCl (19.5 g, 460 mmol). The solutionwas warmed to 125° C. and the mixture was stirred overnight. The mixturewas cooled to ambient temperature and partitioned between EtOAc (2.5 L)and water:brine (1:1, 2.0 L). The mixture was filtered through activatedcharcoal over Celite, which was washed with EtOAc, forming visiblelayers. The organic layer was dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by column chromatography(10 to 80% EtOAc/hexanes) providing 4.5 g (21%) of the product as athick pale orange oil.

Step C: Preparation of tert-butyl3-fluoro-4-hydroxyazepane-1-carboxylate:

To a solution of the product from Step B (0.300 g, 1.30 mmol) in MeOH (6mL) at 0° C. was added NaBH₄ (0.123 g, 3.24 mmol) in one portion, andthe mixture was warmed to ambient temperature and stirred for 5.0 hours.The mixture was concentrated and the residue was taken up in EtOAc (20mL) and a saturated aqueous NH₄Cl solution (5 mL) and water (5 mL). Thelayers were mixed and separated and the aqueous phase extracted withEtOAc (2×10 mL). The combined organic extracts were washed with brineand dried over Na₂SO₄, then filtered and concentrated. The crude productwas purified by column chromatography (12% to 60% EtOAc/hexanesgradient) to provide 0.130 g (43%) of the major isomer as a colorlessoil that solidified overnight to a white solid.

Step D: Preparation of tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-3-fluoroazepane-1-carboxylate:Prepared as described in Example 9 using tert-butyl3-fluoro-4-hydroxyazepane-1-carboxylate in place of tert-butyl4-hydroxypiperidine-1-carboxylate in Step A, substituting THF:Toluene(1:1) for THF and using DIAD in place of DEAD.

Step E: Preparation of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(3-fluoroazepan-4-yloxy)quinolinedihydrochloride: To a solution of the product from Step D (0.10 g, 0.21mmol) in CHCl₃ (2.1 mL) was added HCl (2.1 mL, 8.4 mmol, 4.0M in1,4-Dioxane) and the reaction was stirred at ambient temperature for 5.0hours. The resulting off-white suspension was directly filtered and thesolid was washed with Et₂O and dried in vacuo. This provided 0.089 g(88%) of the desired product as an off-white solid. MS ESI (+) m/z 378.1(M+1) detected.

Example 52

2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(azepan-4-yloxy)quinolinedihydrochloride

Step A: Preparation of tert-butyl 4-hydroxyazepane-1-carboxylate: Asolution of tert-butyl 4-oxoazepane-1-carboxylate (0.60 g, 2.81 mmol),in MeOH (11 mL) was cooled to 0° C. NaBH₄ (0.266 g, 7.03 mmol) was addedand the mixture was slowly warmed to ambient temperature where thereaction stirred overnight. The mixture was concentrated in vacuo andthe residue was taken up in EtOAc (20 mL) and saturated aqueous NH₄Clsolution (20 mL). The layers were separated and the aqueous phase wasextracted with EtOAc (2×10 mL). The combined organic extracts werewashed with brine and dried over Na₂SO₄, then filtered and concentrated.The product was isolated as a thick colorless oil that solidifiedovernight to a white solid.

Step B: Preparation of tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)azepane-1-carboxylate:Prepared as described in Example 9 using tert-butyl4-hydroxyazepane-1-carboxylate in place of tert-butyl4-hydroxypiperidine-1-carboxylate in Step A and substituting THF:Toluene(1:1) for THF and using DIAD in place of DEAD.

Step C: Preparation of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(azepan-4-yloxy)quinolinedihydrochloride: To a solution of the product from Step B (0.40 g, 0.870mmol) in CHCl₃ (9 mL) was added hydrogen chloride (7.62 mL, 30.5 mmol,4.0 M in dioxane) and the reaction was stirred at ambient temperaturefor 5 hours. The resulting yellow solid was removed by direct filtrationand the solid was washed with Et₂O and dried in vacuo to provide 0.296 g(72%) of the desired product as a yellow solid. MS ESI (+) m/z 360.1(M+1) detected.

Example 53

(2S,4S)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-1-(tert-butoxycarbonyl)piperidine-2-carboxylicacid

Step A: Preparation of (2S,4S)-di-tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)piperidine-1,2-dicarboxylate:Prepared as described in Example 9 using di-tert-butyl(2S,4R)-4-hydroxy-1,2-piperidinedicarboxylate (prepared as described inJ. Org. Chem. 2004, 69, 130) in place of tert-butyl4-hydroxypiperidine-1-carboxylate in Step A and using DIAD in place ofDEAD.

Step B: Preparation of(2S,4S)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-1-piperidine-2-carboxylicacid: A solution of the product from Step A (1.3 g, 2.38 mmol) in TFA(6.42 mL, 83.4 mmol) was stirred at ambient temperature for 6 hours atwhich time the reaction was complete by HPLC. TFA was co-evaporated withhexanes and the residue was triturated with Et₂O and filtered. The solidwas washed with Et₂O and dried in vacuo and taken on directly to thenext step.

Step C: Preparation of(2S,4S)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-1-(tert-butoxycarbonyl)piperidine-2-carboxylicacid: The product from Step B was then dissolved in THF (7 mL) and H₂O(3 mL) and was treated with NaOH (1.59 mL, 4.77 mmol, 3.0 M aqueous).Boc₂O (0.780 g, 3.57 mmol) was added and the reaction was stirred atambient temperature overnight. THF was removed in vacuo and the residuewas dissolved in water (20 mL) and Et₂O (10 mL). The layers were mixedand separated and the aqueous phase extracted with Et₂O (3×10 mL). Theaqueous phase was adjusted to pH=2 with 1N KHSO₄. The acidic mixture wasextracted with EtOAc (75 mL then 3×25 mL). The combined organic layerswere washed with water and brine, and the combined aqueous phases werewashed with EtOAc (50 mL). The combined organic layers were then driedover Na₂SO₄, filtered and concentrated to afford 1.06 g (70% pure, 63%yield) of the product. MS ESI (+) m/z 489.9 (M) detected.

Example 54

(2S,4S)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-N,N-dimethylpiperidine-2-carboxamidedihydrochloride

Step A: Preparation of (2S,4S)-tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2-(dimethylcarbamoyl)piperidine-1-carboxylate:(2S,4S)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-1-(tert-butoxycarbonyl)piperidine-2-carboxylicacid (Example 53; 0.100 g, 0.204 mmol), EDCI (0.0548 g, 0.286 mmol) andHOBT (0.0373 g, 0.276 mmol) were mixed in CH₂Cl₂ (2.5 mL) and themixture was cooled to 0° C. Triethylamine (0.0712 mL, 0.511 mmol) wasadded and the mixture stirred for 15 minutes. Dimethylamine (0.153 mL,0.306 mmol, 2.0M in THF) was added, and the mixture was warmed toambient temperature and stirred for 5.0 hours. The mixture was dilutedwith EtOAc (20 mL) and washed with 1N KHSO₄ (2×10 mL), followed bysaturated aqueous NaHCO₃, and brine. The organics were dried over MgSO₄,filtered and concentrated, then purified by column chromatography (1 to5% MeOH/CH₂Cl₂) to afford 0.080 g (75%) of the desired product.

Step B: Preparation of(2S,4S)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-N,N-dimethylpiperidine-2-carboxamidedihydrochloride: To the product from Step A (0.080 g, 0.155 mmol) wasadded chloroform (1.6 mL). To the resulting solution was added hydrogenchloride (0.387 mL, 1.55 mmol, 4.0 M in 1,4-dioxane) causing thesolution to turn yellow. The mixture was stirred at ambient temperaturefor 3 hours. Additional hydrogen chloride (0.387 mL, 1.55 mmol, 4.0 M in1,4-dioxane) was added and the reaction stirred at ambient temperaturefor another 3 hours. The mixture was diluted with diethyl ether (5 mL)and filtered. The product was washed with Et₂O and dried in vacuo toprovide 0.068 g (86%) of the desired product as a yellow solid. MS ESI(+) m/z 417.1 (M+1) detected.

Example 55

(2S,4S)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-N-methoxy-N-methylpiperidine-2-carboxamidedihydrochloride

Step A: Preparation of (2S,4S)-tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate:(2S,4S)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-1-(tert-butoxycarbonyl)piperidine-2-carboxylicacid (Example 53; 0.100 g, 0.204 mmol), EDCI (0.0548 g, 0.286 mmol) andHOBT (0.0359 g, 0.266 mmol) were mixed in CH₂Cl₂ (2.5 mL) and themixture was cooled to 0° C. Triethylamine (0.0712 mL, 0.511 mmol) wasadded and the mixture was stirred for 15 minutes. Dimethyl hydroxylamineHCl (0.0299 g, 0.306 mmol) was added, and the mixture was warmed toambient temperature and stirred for 4.5 hours. The mixture was dilutedwith EtOAc (20 mL) and washed with 1N KHSO₄ (2×10 mL), followed by asaturated aqueous NaHCO₃ solution and brine. The organic layer was driedover Na₂SO₄, filtered and concentrated. The crude material was purifiedby column chromatography (1 to 5% MeOH/CH₂Cl₂) to provide 0.076 g (70%)of the product as a white foam.

Step B: Preparation of(2S,4S)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-N-methoxy-N-methylpiperidine-2-carboxamidedihydrochloride: To the product from Step A (0.032 g, 0.0601 mmol) wasadded CHCl₃ (0.600 mL) and HCl (0.451 mL, 1.80 mmol, 4.0M in dioxane).The mixture was stirred at ambient temperature for 9 hours, then dilutedwith Et₂O (5 mL) and filtered. The solid was washed with Et₂O and driedin vacuo. This provided 0.026 g (82%) of the desired product as a paleyellow solid. MS ESI (+) m/z 433.1 (M+1) detected.

Example 56

((2S,4S)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)piperidin-2-yl)methanoldihydrochloride

Step A: Preparation of (2S,4S)-tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2-(hydroxymethyl)piperidine-1-carboxylate:(2S,4S)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-1-(tert-butoxycarbonyl)piperidine-2-carboxylicacid (Example 53; 0.250 g, 0.511 mmol) was dissolved in THF (5.0 mL) andthe mixture was cooled to 0° C. BH₃—SMe₂ (0.242 mL, 2.55 mmol) was addedand the mixture was warmed to ambient temperature and stirred for 27hours. The reaction was quenched with MeOH (2 mL) and concentrated. Theresidue was taken up in EtOAc (30 mL), water (5 mL) and a saturatedaqueous Na₂CO3 solution (5 mL). The layers were mixed and separated andthe aqueous phase washed once with CH₂Cl₂ (10 mL). The combined organicphases were washed with brine, dried over Na₂SO₄, filtered andconcentrated. During concentration a precipitate formed which wasslurried in MeOH, isolated by filtration and washed with Et₂O to give0.119 g (49%) of the desired product as a pale yellow solid.

Step B: Preparation of((2S,45)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)piperidin-2-yl)methanoldihydrochloride: The product from Step A (0.017 g, 0.036 mmol) wasdissolved in CHCl₃ (1.0 mL). HCl (0.27 mL, 1.1 mmol, 4.0M in dioxane)was added. The reaction stirred at ambient temperature for 7 hours. Thereaction was diluted with Et₂O (10 mL) and the mixture filtered. Thesolid was washed with Et₂O and dried in vacuo to afford 0.0098 g (55%)of the desired product as an off-white solid. MS ESI (+) m/z 376.1 (M+1)detected.

Example 57

2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8)-((2S,4S)-2-(methoxymethyl)piperidin-4-yloxy)quinoline

Step A: Preparation of (2S,4S)-tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2-(hydroxymethyl)piperidine-1-carboxylate:(2S,4S)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-1-(tert-butoxycarbonyl)piperidine-2-carboxylicacid (Example 53; 0.250 g, 0.511 mmol) and THF (5.0 mL) was stirred for10 minutes (until solution was complete) and cooled to 0° C. BH₃—SMe₂(0.242 mL, 2.55 mmol) was added and the mixture was warmed to ambienttemperature and for 48 hours. The reaction was carefully quenched withMeOH (1 mL) and concentrated. The residue was taken up in CH₂Cl₂ (20mL), water (5 mL) and saturated aqueous Na₂CO₃ (5 mL). The layers weremixed and separated and the aqueous phase was washed with CH₂Cl₂ (10mL). The combined organic phases were washed with brine, dried overNa₂SO₄, filtered and concentrated. The resulting solid was slurried in25% CH₂Cl₂/Et₂O and filtered to provide 0.140 g (57%) of the desiredproduct as a yellow solid.

Step B: Preparation of (2S,4S)-tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2-(methoxymethyl)piperidine-1-carboxylate:The product from Step A (0.150 g, 0.315 mmol) was dissolved in dry DMF(2.1 mL) and the solution was cooled to 0° C. NaH (0.0159 g, 0.631 mmol)was added and the mixture was stirred at 0° C. for 1 hour. The reactioncolor went from yellow to a dark red/brown. MeI (0.197 mL, 3.15 mmol)was added and the mixture was warmed to ambient temperature and stirredfor 2.0 hours during which the reaction color became lighter. Themixture was diluted with saturated aqueous NaHCO₃ (10 mL) and themixture was extracted with CH₂Cl₂ (3×10 mL). The combined organic phaseswere washed with brine and dried over Na₂SO₄, then filtered andconcentrated. The crude product was passed through a silica gel plug toprovide the crude yellow product (0.280 g), which was slurried in 1:1Et₂O:hexanes and then filtered to provide 0.075 g (48%) of the productas a pale yellow solid.

Step C: Preparation of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((2S,4S)-2-(methoxymethyl)piperidin-4-yloxy)quinoline:The product from Step B (0.070 g, 0.14 mmol) was dissolved in CHCl₃ (1.4mL). Then HCl (1.4 mL, 5.7 mmol, 4.0M in dioxane) was added and themixture stirred at ambient temperature for 5.0 hours. The mixture wasfiltered directly and the solid washed with CH₂Cl₂ followed by Et₂O anddried. The crude solid was purified by preparative TLC (1 mm, 8%MeOH/DCM with 1% NH₃). This provided 0.031 g (56%) of the product as apale orange solid. MS ESI (+) m/z 390.2 (M+1) detected.

Example 58

3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-7-bromoquinolin-8-yloxy)-2,2-dimethylpropan-1-aminedihydrochloride

Step A: Preparation of 7-bromo-2-methylquinolin-8-ol: To a 250 mL flaskwas added toluene (150 mL) and t-BuNH₂ (7.26 mL, 69.1 mmol). Thesolution was cooled to −25° C. and bromine (1.95 mL, 38.0 mmol) wasadded. The solution was cooled to −78° C. and 2-methylquinolin-8-ol (5.5g, 34.6 mmol) was added as a CH₂Cl₂ solution (15 mL). The reactionmixture was gradually warmed to ambient temperature over 6 hours. Themixture was washed with water (50 mL) and treated with 3.0 M aqueousNaOH (250 mL). This provided copious amounts of precipitate, which wentinto solution after about 600 mL water were added. The layers were mixedand separated. The alkaline extract was carefully acidified withconcentrated HCl(˜50 mL). The solution was extracted with CH₂Cl₂ (4×200mL), the combined extracts were washed with brine and dried over Na₂SO₄,filtered and concentrated. The original water wash was found to containa significant amount of product, so 10 mL 1M HCl were added and theacidic solution was extracted with CH₂Cl₂ (2×75 mL) and these layerswere also washed with brine, dried over Na₂SO₄, filtered andconcentrated. The organic phases were combined to provide 5.01 g (60%)of the desired product as a red/brown solid.

Step B: Preparation of7-bromo-8-(tert-butyldimethylsilyloxy)-2-methylquinoline: To the productfrom Step A (3.0 g, 12.6 mmol) was added imidazole (1.89 g, 27.7 mmol)and CH₂Cl₂ (40 mL). The solution was cooled to 0° C. and thentert-butylchlorodimethylsilane (2.09 g, 13.9 mmol) was added in oneportion. The reaction was gradually warmed to ambient temperature over 1hour then stirred overnight. The mixture was diluted with a saturatedaqueous NH₄Cl solution (25 mL) and CH₂Cl₂ (40 mL). The layers were mixedand separated and the organic layer was washed with brine and dried overNa₂SO₄, filtered and concentrated. The crude product was purified bycolumn chromatography (2 to 20% CH₂Cl₂/hexanes) to provide 3.36 g (76%)of the desired product as a white solid.

Step C: Preparation of7-bromo-8-(tert-butyldimethylsilyloxy)quinoline-2-carbaldehyde: A slurryof SeO₂ (0.869 g, 7.83 mmol) and 1,4-dioxane (20 mL) was warmed to 80°C. and the product from Step B (2.3 g, 6.53 mmol) was added as a1,4-dioxane solution (20 mL). The mixture was stirred at 80° C. for 32hours and then cooled to ambient temperature and filtered through GF/Ffilter paper. The residual solid was washed with CH₂Cl₂, and thefiltrate was concentrated and purified by passing through a silica gelplug, eluting with 50% CH₂Cl₂/hex to provide 2.14 g (89%) of the productas a yellow/orange solid.

Step D: Preparation of7-bromo-8-(tert-butyldimethylsilyloxy)-2-((2-(pyridin-2-yl)hydrazono)methyl)quinoline:To the product from Step C (2.95 g, 8.05 mmol) was added EtOH (30 mL,anhydrous). To this solution was added 2-hydrazinylpyridine (0.967 g,8.86 mmol). The mixture was stirred at ambient temperature for 24 hours.The resulting precipitate was isolated by vacuum filtration, washed withcold EtOH and then dried in vacuo to afford 2.98 g (73%) of the product.

Step E: Preparation of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-7-bromo-8-(tert-butyldimethylsilyloxy)quinoline:To the product from Step D (2.95 g, 6.45 mmol) was added CH₂Cl₂ (60 mL).Iodobenzene diacetate (2.28 g, 7.09 mmol) was added and the mixturestirred at ambient temperature overnight. The mixture was concentratedand the product purified directly by column chromatography (1 to 8%MeOH/CH₂Cl₂) to afford 2.87 g (88%) of the product.

Step F: Preparation of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-7-bromoquinolin-8-ol: To the product from Step E (2.8 g, 6.15 mmol) was addedTHF (60 mL). The solution was cooled to 0° C. then TBAF.3H₂O (2.33 g,7.38 mmol) was added and the mixture was stirred for 1 hour. The mixturewas then diluted with EtOAc (100 mL) and then washed with saturatedaqueous NaHCO₃ (75 mL). The layers were separated and the aqueous phasewashed with EtOAc (100 mL). The combined organic phases were washed withbrine and dried over Na₂SO₄, filtered and concentrated. The crudemixture was triturated with MeOH and filtered. The solid was washed withEt₂O to provide 0.730 g (35%) of product.

Step G: Preparation of tert-butyl 3-(24[1,2,4]triazolo[4,3-a]pyridin-3-yl)-7-bromoquinolin-8-yloxy)-2,2-dimethylpropylcarbamate:Prepared as described in Example 9 using tert-butyl3-hydroxy-2,2-dimethylpropylcarbamate in place of tert-butyl4-hydroxypiperidine-1-carboxylate in Step A. The crude product was useddirectly in the next step.

Step H: Preparation of 3-(24[1,2,4]triazolo[4,3-a]pyridin-3-yl)-7-bromoquinolin-8-yloxy)-2,2-dimethylpropan-1-aminedihydrochloride: To the product from Step G (0.115 g, 0.143 mmol,isolated as a mixture with triphenylphosphine oxide) was added CHCl₃(1.5 mL). To this solution was added HCl (1.43 mL, 5.72 mmol, 4.0M indioxane) and the mixture was stirred at ambient temperature for 2.5hours. The mixture was diluted with CH₂Cl₂ (2 mL) and filtered directlyand the resulting solid was washed with CH₂Cl₂ (5 mL) and then withEt₂O. The solid was dried to provide 0.059 g (81%) of the desiredproduct as the di-HCl salt free from triphenylphosphine oxide and as anoff-white solid. MS ESI (+) m/z 426.1 (M+H) detected.

Example 59

2-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((cis)-3-fluoropiperidin-4-yloxy)quinoline

Step A: Preparation of 5-fluoro-2-hydrazinylpyridine:2-chloro-5-fluoropyridine (5.00 g, 38.01 mmol) was combined withhydrazine monohydrate (15 mL, 303.0 mmol) in a Teflon® lined reactor.The reaction was purged with argon gas and sealed, then heated to 200°C. overnight. Following overnight heating, the reaction mixture wasevaporated to solids under reduced pressure, and then dissolved in watercontaining NaHCO₃. The mixture was transferred to a reparatory funnel,and extracted 4 times with EtOAc. The combined organic extracts weredried over Na₂SO₄, filtered and concentrated to residue under reducedpressure, followed by purification by flash column chromatographyeluting with 5% MeOH 0.5% NH₄OH in DCM to give the desired5-fluoro-2-hydrazinylpyridine (1.50 g, 31% yield). MS APCI (+) m/z 128.0(M+1) detected.

Step B: Preparation of8-(tert-butyldimethylsilyloxy)quinoline-2-carbaldehyde: A solution of8-hydroxyquinoline-2-carbaldehyde (10.00 g, 57.75 mmol) and imidazole(8.649 g, 127.0 mmol) in DCM (290 mL, 57.75 mmol) was cooled to 0° C. onan ice bath. TBDMS-Cl (9.574 g, 63.52 mmol) was added and the reactionstirred overnight at ambient temperature. Water was added and thereaction transferred to a separatory funnel. The aqueous phase wasextracted 3 times with DCM, the organics combined, followed by washeswith water and brine. The combined organic layers were dried overNa₂SO₄, filtered and concentrated to residue under reduced pressure. Theresidue was purified by flash column chromatography, eluting with 25%EtOAc/Hexanes to give the product (12.2 g, 74% yield). MS APCI (+) m/z288.1 (M+1) detected.

Step C: Preparation of8-(tert-butyldimethylsilyloxy)-2-(6-fluoro[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline:8-(tert-butyldimethylsilyloxy)quinoline-2-carbaldehyde (1.39 g, 4.83mmol) and 5-fluoro-2-hydrazinylpyridine (1.28 g, 6.04 mmol) werecombined in DCM (12.1 mL, 4.83 mmol) at ambient temperature and stirredfor 15 minutes. The mixture was cooled to 0° C. followed by addition ofiodobenzene diacetate (IBD; 1.87 g, 5.80 mmol). The reaction was warmedto ambient temperature and stirred overnight. Additional IBD (0.8equivalents, 4.64 mmol) was added and the reaction was allowed to stirat ambient temperature for 48 hours total. The mixture was transferredto a separatory funnel, diluting with water and DCM. The organic phasewas washed with saturated aqueous Na₂SO₃, followed by back extraction ofthe aqueous phase 2 times with DCM. The organics were combined andwashed with brine, dried over Na₂SO₄, filtered and concentrated to aresidue under reduced pressure, followed by purification by flash columnchromatography to give the product (1.08 g, 57% yield). MS APCI (+) m/z395.3 (M+1) detected.

Step D: Preparation of2-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol: A solutionof8-(tert-butyldimethylsilyloxy)-2-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline(560 mg, 1.4195 mmol) in THF (10.13 mL, 1.267 mmol) was cooled to 0° C.in an ice bath. TBAF (1M in THF, 2.122 mL, 2.129 mmol) was added bysyringe and the mixture stirred for 1 hour at 0° C. Water was added,followed by saturated aqueous NaHCO₃ solution. The mixture wastransferred to a separatory funnel, diluting with EtOAc and water. Themixture was extracted with EtOAc, the combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography eluting with 10-15% MeOH 1% NH₄OH in EtOAc to give theproduct as a yellow film (35 mg, 9% yield). MS APCI (+) m/z 281.2 (M+1)detected.

Step E: Preparation of (cis)-tert-butyl3-fluoro-4-(2-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)piperidine-1-carboxylate:A mixture of (trans)-tert-butyl3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylate (24 mg, 0.0807mmol), 2-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol(23.8 mg, 0.0850 mmol) and Cs₂CO₃ (55.4 mg, 0.170 mmol) in DMA (425 μl,0.0850 mmol) was heated to 90° C. for 16 hours. The mixture wastransferred to a reparatory funnel and diluted with EtOAc and water. Themixture was then extracted with EtOAc, and the combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentrated toa residue under reduced pressure to give the product without furtherpurification (33 mg, 81% yield). MS APCI (+) m/z 481.9 (M+1) detected.

Step F: Preparation of2-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((cis)-3-fluoropiperidin-4-yloxy)quinoline:(cis)-tert-butyl3-fluoro-4-(2-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)piperidine-1-carboxylate(33 mg, 0.069 mmol) was dissolved in 2 mL DCM at ambient temperature.TFA (2 mL) was added and the mixture stirred at ambient temperature 1hour. The reaction was evaporated under reduced pressure, and purifiedby preparative TLC eluting with 1:10 mixture of (0.5% NH₄OH in MeOH):DCMto give the product (4.5 mg, 17% yield). MS APCI (+) m/z 382.1 (M+1)detected.

Example 60

cis-2-(7-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-3-fluoropiperidin-4-yloxy)quinoline

Prepared as described in Example 59 using 4-fluoro-2-hydrazinylpyridine(as prepared in: JOC, 2005, 70: 2494) in place of5-fluoro-2-hydrazinylpyridine. MS ESI (+) m/z 382.2 (M+1) detected.

Example 61

(S)-2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(pyrrolidin-2-ylmethoxy)quinoline

Prepared as described in Example 25 using (S)-tert-butyl2-((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate in place of(cis)-tert-butyl-3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylate.Boc deprotection was achieved as described in Example 9, Step B. MS ESI(+) m/z 346.2 (M+1) detected.

Example 62

3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)propane-1,2-diol

Prepared as described in Example 9, Step A, using(2,2-dimethyl-1,3-dioxolan-4-yl)methanol in place of tert-butyl4-hydroxypiperidine-1-carboxylate. Ketal deprotection was achieved asdescribed in Example 9, Step B, using aqueous HCl in place of TFA/DCM.MS ESI (+) m/z 337.1 (M+1) detected.

Example 63

3-(2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethylpropan-1-aminedihydrochloride

Step A: Preparation of2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(tert-butyldimethylsilyloxy)-quinoline:Prepared as described in Example 1, Steps A-C, using5-bromo-2-hydrazinylpyridine in place of 2-hydrazinylpyridine.

Step B: Preparation of2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol: Prepared asdescribed in Example 1, Step D, using2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(tert-butyldimethylsilyloxy)-quinolinein place of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(tert-butyldimethylsilyloxy)-.

Step C: Preparation of tert-butyl3-(2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethylpropylcarbamate:Prepared as described in Example 9, Step A, using tert-butyl3-hydroxy-2,2-dimethylpropylcarbamate in place oftert-butyl-4-hydroxypiperidine-1-carboxylate and2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol in place of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol.

Step D: Preparation of3-(2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethylpropan-1-aminedihydrochloride: To a solution of tert-butyl3-(2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethylpropylcarbamate(0.108 g, 0.205 mmol) in 2 mL dichloromethane was added neat TFA (0.395mL, 5.13 mmol). The reaction mixture was stirred at ambient temperaturefor 4 hours, after which it was concentrated. The residue wasconcentrated twice from dichloromethane/hexanes to give solids, whichwere dried in vacuo. The solids were dissolved in several drops ofmethanol and minimal dichloromethane, and this solution was added to avigorously stirring solution of 20 mL ether and 1.5 mL 2M HCl/ether,causing precipitation. The solids were stirred 5 minutes, then isolatedby filtration through a medium glass fitted funnel by pushing thesolvent through the funnel with nitrogen pressure, rinsed twice withether, twice with 1:1 dichloromethane:ether, twice with ether, and driedin vacuo to give the title compound (0.042 g, 0.0841 mmol, 41.0% yield)as a pale yellow powder. MS APCI (+) m/z 426/428 (M+1)(Br isotope)detected.

Example 64

3-(2-(6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethylpropan-1-aminedihydrochloride

Step A: Preparation of8-(tert-butyldimethylsilyloxy)-2-(6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline:2-(6-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(tert-butyldimethylsilyloxy)quinoline(0.500 g, 1.10 mmol), cyclopropylboronic acid (0.123 g, 1.43 mmol),Pd(OAc)₂ (0.012 g, 0.0549 mmol), P(Cy)₃ (0.031 g, 0.110 mmol), and K₃PO₄(0.699 g, 3.29 mmol) were combined with 5.5 mL toluene and 0.55 mL H₂O(both degassed with nitrogen 30 minutes prior to use). The mixture wassonicated and put on a 100° C. reaction block and stirred for 3 hours.The reaction mixture was cooled to ambient temperature, diluted withtoluene, vacuum filtered through compressed Celite, rinsed with toluene,and the filtrate was concentrated. The crude material was purified onsilica (5% to 60% ethyl acetate in dichloromethane) to give the titlecompound (0.159 g, 0.382 mmol, 34.8% yield) as a brown foam.

Step B: Preparation of2-(6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol: To a0° C. solution of8-(tert-butyldimethylsilyloxy)-2-(6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline(0.159 g, 0.382 mmol) in 4 mL THF was added solid TBAF hydrate (0.150 g,0.573 mmol), causing the reaction mixture to turn cloudy. The reactionmixture was warmed to ambient temperature after 5 minutes and thenstirred 17 hours, after which it was diluted with saturated NH₄Cl andwater, causing solids to form. The solids were isolated by vacuumfiltration through a Buchner funnel, rinsed with water, and air dried invacuo to give the title compound (0.072 g, 0.238 mmol, 62.4% yield) as alight pink powder.

Step C: Preparation of tert-butyl3-(2-(6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethylpropylcarbamate:Prepared as described in Example 9, Step A, using tert-butyl3-hydroxy-2,2-dimethylpropylcarbamate in place oftert-butyl-4-hydroxypiperidine-1-carboxylate and2-(6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol inplace of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol.

Step D: Preparation of3-(2-(6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethylpropan-1-aminedihydrochloride: Prepared as described in Example 63, Step D, usingtert-butyl3-(2-(6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethylpropylcarbamatein place of tert-butyl3-(2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethylpropyl-carbamate.MS APCI (+) m/z 388 (M+1) detected.

Example 65

2,2-Dimethyl-3-(2-(6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)propan-1-aminedihydrochloride

Step A: Preparation of2-(6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol:2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(tert-butyldimethylsilyloxy)quinoline(0.500 g, 1.10 mmol), phenylboronic acid (0.167 g, 1.37 mmol), Pd(PPh₃)₄(0.0634 g, 0.0549 mmol), and 2M aqueous Na₂CO₃ (2.74 mL, 5.49 mmol)(degassed with nitrogen 30 minutes prior to use) were combined with 7 mLdioxane (degassed with nitrogen 30 minutes prior to use), sonicated, andheated to 110° C. in a reaction block for 18 hours, during which thereaction went dry. The reaction mixture was cooled to ambienttemperature, diluted with DMF, and the suspension was vacuum filteredthrough compressed Celite, rinsed with DMF, and the filtrate wasconcentrated. The crude material was purified on silica gel (1-20%methanol in dichloromethane gradient) to give the title compound (0.138g, 0.408 mmol, 37.1% yield) as a brown solid.

Step B: Preparation of tert-butyl2,2-dimethyl-3-(2-(6-phenyl-[1,2,4]triazolo[4,3-a]pyridine-3-yl)quinolin-8-yloxy)propylcarbamate:Prepared as described in Example 9, Step A, using tert-butyl3-hydroxy-2,2-dimethylpropylcarbamate in place oftert-butyl-4-hydroxypiperidine-1-carboxylate and2-(6-phenyl-[1,2,4]triazolo[4,3-a]pyridine-3-yl)quinolin-8-ol in placeof 2-([1,2,4]triazolo[4,3-a]pyridine-3-yl)quinolin-8-ol.

Step C: Preparation of2,2-dimethyl-3-(2-(6-phenyl-[1,2,4]triazolo[4,3-a]pyridine-3-yl)quinolin-8-yloxy)propan-1-aminedihydrochloride: Prepared as described in Example 63, Step D, usingtert-butyl2,2-dimethyl-3-(2-(6-phenyl-[1,2,4]triazolo[4,3-a]pyridine-3-yl)quinolin-8-yloxy)propylcarbamatein place of tert-butyl3-(2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-yl)quinolin-8-yloxy)-2,2-dimethylpropyl-carbamate.MS APCI (+) m/z 424 (M+1) detected.

Example 66

2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-fluoropiperidin-4-yl)methoxy)quinolinedihydrochloride

Step A: Preparation of tert-butyl4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate: To a 0° C. solutionof 1-tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate (3.0 g,10.90 mmol) in 55 mL THF was added 1M lithium aluminum hydride in THF(21.79 mL, 21.79 mmol). The reaction mixture was stirred at 0° C. for3.5 hours, after which it was carefully quenched by the addition of 1:1Na₂SO₄-10H₂O:Celite, diluted with THF, warmed to ambient temperature,and stirred vigorously for 2 hours. The slurry was vacuum filteredthrough GF/F paper on a Buchner funnel, rinsed with THF, and thefiltrate was concentrated in vacuo to give the title compound (2.69 g)as a clear colorless oil, which was used without further purification.

Step B: Preparation of tert-butyl4-fluoro-4-((methylsulfonyloxy)methyl)piperidine-1-carboxylate: To a 0°C. solution of tert-butyl4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (2.60 g, 11.1 mmol)and triethylamine (2.33 mL, 16.7 mmol) in 55 mL dichloromethane wasadded neat methanesulfonyl chloride (0.949 mL, 12.3 mmol) dropwise bysyringe. The reaction mixture was slowly warmed to ambient temperatureand stirred at ambient temperature for 17 hours. Saturated NaHCO₃ wasadded, the mixture was extracted with dichloromethane, and combinedextracts were dried (Na₂SO₄), filtered, and concentrated. The crude waspurified on silica gel (4:1 hexanes:ethyl acetate to 1:1 hexanes:ethylacetate) to give the title compound (3.2 g, 92.2% yield) as a whitepowder.

Step C: Preparation of tert-butyl4-42-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-4-fluoropiperidine-1-carboxylate:Prepared as described in Example 23 using tert-butyl4-fluoro-4-((methylsulfonyloxy)methyl)piperidine-1-carboxylate in placeof neopentyl iodide. MS APCI (+) m/z 478 (M+1) detected.

Step D: Preparation of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-fluoropiperidin-4-yl)methoxy)quinolinedihydrochloride: Prepared as described in Example 63, Step D, usingtert-butyl4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-4-fluoropiperidine-1-carboxylatein place of tert-butyl3-(2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-yl)quinolin-8-yloxy)-2,2-dimethylpropyl-carbamate.MS APCI (+) m/z 378 (M+1) detected.

Example 67

2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-methylpiperidin-4-yl)methoxy)quinolinedihydrochloride

Step A: Preparation of tert-butyl4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-4-methylpiperidine-1-carboxylate:Prepared according to the method of Example 66, Steps A-C, using1-tert-butyl 4-ethyl 4-methylpiperidine-1,4-dicarboxylate in place of1-tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate. MS APCI (+)m/z 474 (M+1) detected.

Step B: Preparation of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-methylpiperidin-4-yl)methoxy)quinolinedihydrochloride: Prepared according to the method of Example 63, Step D,using tert-butyl4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-4-methyl-piperidine-1-carboxylatein place of tert-butyl3-(2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-yl)quinolin-8-yloxy)-2,2-dimethylpropyl-carbamate.MS APCI (+) m/z 374 (M+1) detected.

Example 68

2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-ethylpiperidin-4-yl)methoxy)quinolinedihydrochloride

Step A: Preparation of 1-tert-butyl 4-ethyl4-ethylpiperidine-1,4-dicarboxylate: To a 0° C. solution of methylpiperidine-4-carboxylate (2.0 g, 14.0 mmol) in 35 mL THF was added 1MLHMDS in THF (27.9 mL, 27.9 mmol). The reaction mixture was stirred at0° C. for 90 minutes, then neat iodoethane (3.91 mL, 48.9 mmol) wasadded slowly by syringe. The reaction mixture was stirred 10 minutes,warmed to ambient temperature, and stirred 18 hours. Saturated NH₄Cl wasadded, the mixture was extracted with ethyl acetate, and the combinedextracts were dried (Na₂SO₄), filtered, and concentrated. The crude waspurified on silica gel eluting with 10:1 hexanes:ethyl acetate to givethe title compound (0.843 g, 3.11 mmol, 22.2% yield) as a clear,colorless oil.

Step B: Preparation of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-ethylpiperidin-4-yl)methoxy)quinolinedihydrochloride: Prepared as described for Example 66 using 1-tert-butyl4-ethyl 4-methylpiperidine-1,4-dicarboxylate in place of 1-tert-butyl4-ethyl 4-fluoropiperidine-1,4-dicarboxylate. MS APCI (+) m/z 388 (M+1)detected.

Example 69

2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-44-(cyclopropylmethyl)piperidin-4-yl)methoxy)quinolinedihydrochloride

Prepared as described for Example 68 using (bromomethyl)cyclopropane inplace of iodoethane. MS APCI (+) m/z 414 (M+1) detected.

Example 70

2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-isopropylpiperidin-4-yl)methoxy)quinolinedihydrochloride

Prepared as described for Example 68 using 2-iodopropane in place ofiodoethane. MS APCI (+) m/z 402 (M+1) detected.

Example 71

4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-1-benzylpiperidin-4-ol

Prepared as described in Example 23 using6-benzyl-1-oxa-6-azaspiro[2.5]octane in place of neopentyl iodide. MSAPCI (+) m/z 466 (M+1) detected.

Example 72

4-42-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)piperidin-4-olbis(trifluoroacetate)

Step A: Preparation of tert-butyl4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-4-hydroxypiperidine-1-carboxylate:Prepared as described in Example 23 using tert-butyl1-oxa-6-azaspiro[2.5]octane-6-carboxylate in place of neopentyl iodide.

Step B: Preparation of4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-piperidin-4-olbis(trifluoroacetate): To a solution of tert-butyl4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-4-hydroxypiperidine-1-carboxylate(0.006 g, 0.013 mmol) in 0.15 mL dichloromethane was added neat TFA(0.029 mL, 0.37 mmol). The reaction mixture was stirred at ambienttemperature for 5 hours, after which it was concentrated to dryness. Theresidue was dissolved in dichloromethane, and the resulting solution wasadded dropwise to vigorously stirring ether, causing precipitation. Theresulting solids were isolated by filtration through a 0.2 micron nylonfilter disc, rinsed with ether, and dried in vacuo to give the titlecompound (0.005 g, 65.7% yield) as a pale yellow powder. MS APCI (+) m/z376 (M+1) detected.

Example 73

2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-methoxypiperidin-4-yl)methoxy)quinolinebis(trifluoroacetate)

Step A: Preparation of tert-butyl4-42-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-4-methoxypiperidine-1-carboxylate:To a 0° C. suspension of tert-butyl4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-4-hydroxypiperidine-1-carboxylate(0.033 g, 0.069 mmol) in 2 mL DMF was added 60% NaH in mineral oil(0.0117 g, 0.486 mmol). The reaction mixture was warmed to ambienttemperature and stirred 2 hours. Neat iodomethane (0.035 mL, 0.56 mmol)was added, and the reaction mixture was stirred for 21 hours. Thereaction mixture was concentrated, and the residue was diluted withsaturated NH₄Cl and extracted with dichloromethane. The combinedextracts were dried (Na₂SO₄), filtered, and concentrated. The crude waspurified by preparative TLC (0.5 mm plate, 9:1 dichloromethane:methanol)to give the title compound (0.016 g, 47.1% yield) as a yellow residue.

Step B: Preparation of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-methoxypiperidin-4-yl)methoxy)quinolinebis(trifluoroacetate): Prepared as described for Example 72, Step B,using tert-butyl4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-methyl)-4-methoxypiperidine-1-carboxylatein place of tert-butyl4-((2-([1,2,4]triazolo-[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-4-hydroxypiperidine-1-carboxylate.MS APCI (+) m/z 390 (M+1) detected.

Example 74

2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(pyridin-4-yloxy)quinoline

Prepared as described in Example 23 using 4-fluoropyridine hydrochloride(which was converted to the free base in situ withdiisopropylethylamine) in place of neopentyl iodide. MS APCI (+) m/z 340(M+1) detected.

Example 75

4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)pyridin-2-amine

Step A: Preparation of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(2-chloropyridin-4-yloxy)quinoline:Prepared as described in Example 23 using 2-chloro-4-nitropyridine inplace of neopentyl iodide. MS APCI (+) m/z 374 (M+1) detected.

Step B: Preparation of4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)pyridin-2-amine:To a solution of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(2-chloropyridin-4-yloxy)quinoline(0.105 g, 0.281 mmol) in 71 mL THF (degassed with nitrogen 30 minutesprior to use) was added sequentially XPHOS (0.0107 g, 0.0225 mmol), Pd₂dba₃ (0.0103 g, 0.0112 mmol), and 1M LHMDS in THF (0.590 mL, 0.590 mmol)by syringe. The reaction mixture was heated to reflux and stirred for 3hours. The reaction mixture was cooled to 0° C. and 1M aqueous HCl (1.40mL, 1.40 mmol) was added, causing milky solids to form. The reactionmixture was stirred 30 minutes, then diluted with water anddichloromethane, and the aqueous layer was washed with dichloromethane.The aqueous layer was basified with 1M NaOH (pH>10), and the milkymixture was extracted with chloroform. The combined extracts were dried(Na₂SO₄), filtered, and concentrated. The crude was purified bypreparative TLC (9:1 chloroform:6% NH₄OH in methanol) to give the titlecompound (0.027 g, 0.0762 mmol, 27.1% yield) as a yellow/orange powder.MS APCI (+) m/z 355 (M+1) detected.

Example 76

4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)pyrimidin-2-amine

Step A: Preparation of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(2-chloropyrimidin-4-yloxy)quinoline:Prepared as described in Example 23 using 2,4-dichloropyrimidine inplace of neopentyl iodide. MS APCI (+) m/z 375 (M+1) detected.

Step B: Preparation of4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-pyrimidin-2-amine:Prepared as described in Example 75, Step B, using2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(2-chloropyrimidin-4-yloxy)quinolinein place of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(2-chloropyridin-4-yloxy)quinoline.MS APCI (+) m/z 356 (M+1) detected.

Example 77

2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-fluoropiperidin-4-yl)methoxy)-quinolinedihydrochloride

Prepared as described in Example 66 using2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol in place of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol in Step C. MS APCI(+) m/z 456/458 (M+1) (Br isotope) detected.

Example 78

2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((cis)-3-fluoropiperidin-4-yloxy)quinolinedihydrochloride

Prepared as described in Example 66 using(trans)-tert-butyl-3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylatein place of tert-butyl4-fluoro-4-((methylsulfonyloxy)methyl)piperidine-1-carboxylate and2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol in place of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol in Step C. MS APCI(+) m/z 442/444 (M+1) (Br isotope) detected.

Example 79

2-(6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-fluoropiperidin-4-yl)methoxy)quinolinedihydrochloride

Prepared as described in Example 66 using2-(6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol inplace of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol. MS APCI(+) m/z 418 (M+1) detected.

Example 80

2-(6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((cis)-3-fluoropiperidin-4-yloxy)quinolinedihydrochloride

Prepared as described in Example 66 using2-(6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol inplace of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol and(trans)-tert-butyl-3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylatein place of tert-butyl4-fluoro-4-((methylsulfonyloxy)methyl)piperidine-1-carboxylate in StepC. MS APCI (+) m/z 404 (M+1) detected.

Example 81

8((4-fluoropiperidin-4-yl)methoxy)-2-(6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolinedihydrochloride

Prepared as described in Example 66 using2-(6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol in place of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol in Step C. MS APCI(+) m/z 454 (M+1) detected.

Example 82

8-((cis)-3-fluoropiperidin-4-yloxy)-2-(6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolinedihydrochloride

Prepared as described in Example 66 using2-(6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol in place of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol and(trans)-tert-butyl-3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylatein place of tert-butyl4-fluoro-4-((methylsulfonyloxy)methyl)piperidine-1-carboxylate in StepC. MS APCI (+) m/z 440 (M+1) detected.

Example 83

2-(4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-4-fluoropiperidin-1-yl)acetamide

To a suspension of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-fluoropiperidin-4-yl)methoxy)quinolinedihydrochloride (0.050 g, 0.111 mmol) and TEA (0.0619 mL, 0.444 mmol) in0.4 mL THF, 0.3 mL dichloromethane, and 0.2 mL DMF was added2-bromoacetamide (0.0184 g, 0.133 mmol). The reaction mixture was heatedin a 40° C. reaction block and stirred 1 hour. The reaction mixture wascooled to ambient temperature, several drops of saturated NaHCO₃ wereadded, and the milky mixture was heated back to 40° C. and stirredanother 3 hours. The reaction mixture was cooled to ambient temperature,diluted with water, and the resulting solids were collected by vacuumfiltration through a 0.2 micron nylon filter disc, rinsed with water,air dried, then washed successively with ethyl acetate, dichloromethane,and ether, air dried, and dried in vacuo to give the title compound(0.014 g, 0.0322 mmol, 29.0% yield) as a white powder. MS APCI (+) m/z435 (M+1) detected.

Example 84

2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-fluoro-1-methylpiperidin-4-yl)methoxy)quinolinedihydrochloride

To a suspension of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-fluoropiperidin-4-yl)methoxy)quinolinedihydrochloride (0.050 g, 0.111 mmol) and triethylamine (0.0619 mL,0.444 mmol) in 0.6 mL DCE and 0.3 mL DMF was added 37% formaldehyde inwater (0.0413 mL, 0.555 mmol). After stirring at ambient temperature for15 minutes, Na(OAc)₃BH (0.0471 g, 0.222 mmol) was added, and thereaction mixture was stirred at ambient temperature for 18 hours.Another 10 equivalents of 37% formaldehyde was added, followed by 10equivalents of Na(OAc)₃BH. The reaction mixture was stirred another 6hours, and saturated NaHCO₃ was added. The mixture was extracted withdichloromethane, and the combined extracts were dried (Na₂SO₄),filtered, and concentrated. The crude was purified by preparative TLC (1mm plate, 6:1 dichloromethane: 6% NH₄OH in methanol). The resultingresidue was dissolved in minimal dichloromethane, and this solution wasadded to a vigorously stirring solution of 1.5 mL 2M HCl/ether in 15 mLether, causing precipitation. The solids were isolated by filtrationthrough a medium glass fritted funnel by pushing the solvent through thefrit with nitrogen pressure, rinsed with ether, dried under nitrogenpressure, and dried in vacuo to give the title compound (0.015 g, 0.0323mmol, 29.1% yield) as a white powder. MS APCI (+) m/z 392 (M+1)detected.

Example 85

2-(4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-4-fluoropiperidin-1-yl)ethanoldihydrochloride

Prepared as described in Example 84 using 2-hydroxyacetaldehyde in placeof 37% formaldehyde. MS APCI (+) m/z 422 (M+1) detected.

Example 86

2-(4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-4-fluoropiperidin-1-yl)ethanoldihydrochloride

Prepared as described in Example 84 using 2-hydroxyacetaldehyde in placeof 37% formaldehyde and2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-methylpiperidin-4-yl)methoxy)quinolinedihydrochloride in place of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-fluoropiperidin-4-yl)methoxy)quinolinedihydrochloride. MS APCI (+) m/z 418 (M+1) detected.

Example 87

(2S,4S)-methyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)pyrrolidine-2-carboxylate

Prepared as described in Example 36 using (2S,4R)-1-tert-butyl 2-methyl4-hydroxypyrrolidine-1,2-dicarboxylate in place (2S,4S)-1-tert-butyl2-methyl 4-hydroxypiperidine-1,2-dicarboxylate. MS ESI (+) m/z 390.1(M+1) detected.

Example 88

2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro-8-((cis)-3-fluoropiperidin-4-yloxy)quinoline

Prepared as described in Example 26 using2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-ol in place of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-quinolin-8-ol. MS ESI (+) m/z382.2 (M+1) detected.

Example 89

(S)-2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro-8-(piperidin-3-ylmethoxy)quinoline

Prepared as described in Example 16 using (S)-tert-butyl3-(hydroxymethyl)piperidine-1-carboxylate in place of tert-butyl3-(hydroxymethyl)piperidine-1-carboxylate, and2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-ol in place of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-quinolin-8-ol. MS ESI (+) m/z378.2 (M+1) detected.

Example 90

Enantiomer 1 ofcis-2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro-8-5-fluoroazepan-4-yloxy)quinoline

Step A: Preparation of trans-tert-butyl4-fluoro-5-hydroxyazepane-1-carboxylate: To a tert-butyl4-fluoro-5-oxoazepane-1-carboxylate (20.0 g, 86.5 mmol) was dissolved inTHF (430 mL) solution and the solution was cooled to −5° C. L-selectride(112 mL, 112 mmol, 1.0 M in THF) was added via syringe. The mixture wasgradually warmed to ambient temperature over 3 hours and stirred for anadditional 20 hours. The resulting cloudy mixture was diluted with 110mL of MeOH which was followed by the addition of NaOH (355 mL, 355 mmol,1.0M aqueous). The mixture was cooled in a water bath, and H₂O₂ (80.4mL, 709 mmol, 30% aqueous) was added carefully via addition funnel over30 minutes. The mixture was stirred vigorously for 1 hour, then dilutedwith water and extracted with EtOAc (3×200 mL). The combined organiclayers were washed with water and 1N KHSO₄ (2×150 mL), and the combinedaqueous phases were back-extracted with EtOAc (200 mL). The combinedorganic layers were washed with saturated aqueous NaHCO₃, then driedover Na₂SO₄, filtered and concentrated. The crude product was purifiedvia column chromatography (15% to 60% EtOAc/hexanes) to provide theproduct as a thick colorless oil which slowly became a white solid (13.9g, 69%; diastereomeric ratio (dr): ˜7:1 trans:cis).

Step B: Preparation of trans-tert-butyl4-fluoro-5-(4-nitrophenylsulfonyloxy)azepane-1-carboxylate:trans-tert-butyl 4-fluoro-5-hydroxyazepane-1-carboxylate (12.36 g, 52.98mmol) was dissolved in CH₂Cl₂ (110 mL). The solution was cooled to 0°C., 4-nitrobenzene-1-sulfonyl chloride (14.09 g, 63.58 mmol) was addedand the mixture was stirred for 10 minutes. NEt₃ (11.08 mL, 79.48 mmol)was added and the mixture was slowly warmed to ambient temperature over1 hour and stirred for an additional 2 hours. The mixture was dilutedwith CH₂Cl₂ and washed with water followed by 1N KHSO₄ (2×50 mL), thenwith saturated aqueous NaHCO₃ (50 mL) and brine, and the combinedorganic layers were dried over Na₂SO₄, filtered and concentrated. Thecrude product was purified via column chromatography (10 to 70%MTBE/hexanes) to provide 18.4 g of the product (84%) as a single isomerand as a faint orange powder.

Step C: Preparation of cis-tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yloxy)-5-fluoroazepane-1-carboxylate: trans-tert-Butyl4-fluoro-5-(4-nitrophenylsulfonyloxy)azepane-1-carboxylate (0.526 g,1.26 mmol) and2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-ol (0.320 g,1.14 mmol) were slurried in CH₃CN (5.5 mL). To this mixture was added2-tert-butyl-1,1,3,3-tetramethylguanidine (0.276 mL, 1.37 mmol)dropwise. The mixture was warmed to 40° C. and stirred overnight. Themixture was cooled to ambient temperature and diluted with water (10 mL)and stirred for 15 minutes, then filtered, and the solid was washed withwater and hexanes and dried. This provided 0.460 g of the title compound(81%) as an off-white solid (>95% pure by HPLC). MS ESI (+) m/z 496.0(M+1) detected.

Step D: Isolation of Enantiomer 1 of cis-tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yloxy)-5-fluoroazepane-1-carboxylate:Racemic cis-tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yloxy)-5-fluoroazepane-1-carboxylate was separated by chiral HPLC on a Prep Chiral OJ-Hcolumn using the following solvent mixture: 75% heptane, 20% EtOH, 3%MeOH, 2% acetonitrile, to provide the enantiomers as peak 1 (7.573minutes) and peak 2 (8.373 minutes). Peak 1 was isolated to provide thetitle compound 99% ee, 99% de. MS ESI (+) m/z 496.0 (M+1) detected.

Step E: Preparation of Enantiomer 1 ofcis-2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro-8-5-fluoroazepan-4-yloxy)quinoline:Enantiomer 1 of cis-tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yloxy)-5-fluoroazepane-1-carboxylate(0.119 g, 0.240 mmol) was dissolved in CHCl₃ (2.4 mL). HCl (2.40 mL,9.61 mmol, 4.0 M dioxane) was added and the mixture was stirred atambient temperature for 3 hours. The mixture was filtered through apolypropylene filter and washed with CH₂Cl₂ and Et₂O, then slurried inhexanes and dried carefully in vacuo to provide 0.095 g of the desiredproduct as a white solid (85%). MS ESI (+) m/z 396.1 (M+1) detected.Specific rotation: [α]²⁵ _(D)=−49.6° (c=0.95, MeOH).

Example 91

Enantiomer 2 oftrans-2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro-8-5-fluoroazepan-4-yloxy)quinoline

Step A: Preparation of trans-tert-butyl4-fluoro-5-hydroxyazepane-1-carboxylate: To a tert-butyl4-fluoro-5-oxoazepane-1-carboxylate (20.0 g, 86.5 mmol) was dissolved inTHF (430 mL) solution and the solution was cooled to −5° C. L-Selectride(112 mL, 112 mmol, 1.0 M in THF) was added via syringe. The mixture wasgradually warmed to ambient temperature over 3 hours and stirred for anadditional 20 hours. The resulting cloudy mixture was diluted with 110mL of MeOH, followed by addition of NaOH (355 mL, 355 mmol, 1.0Maqueous). The mixture was cooled in a water bath and H₂O₂ (80.4 mL, 709mmol, 30% aqueous) was added carefully via addition funnel over 30minutes. The mixture was stirred vigorously for 1 hour. The mixture wasdiluted with water and extracted with EtOAc (3×200 mL). The combinedorganic layers were washed with water and 1N KHSO₄ (2×150 mL), and thecombined aqueous phases were back extracted with EtOAc (200 mL). Thecombined organic layers were washed with saturated aqueous NaHCO₃, driedover Na₂SO₄, filtered and concentrated. The crude product was purifiedvia column chromatography (15% to 60% EtOAc/hexanes) to provide theproduct as a thick colorless oil which slowly became a white solid (13.9g, 69%; diastereomeric ratio (dr): ˜7:1 trans:cis).

Step B: Preparation of cis-tert-butyl4-fluoro-5-hydroxyazepane-1-carboxylate: trans-tert-butyl4-fluoro-5-hydroxyazepane-1-carboxylate (25.00 g, 107.2 mmol) wasdissolved in THF (1100 mL). To this solution was added 2-chloroaceticacid (15.19 g, 160.8 mmol) and PPh₃ (42.16 g, 160.8 mmol). The solutionwas cooled to 0° C. and DEAD (25.31 mL, 160.8 mmol) was added as a THFsolution (250 mL). The reaction mixture was protected from light andstirred overnight as it slowly increased to ambient temperature. The THFwas removed in vacuo and replaced with EtOAc. The solution was washedwith saturated aqueous NaHCO₃, dried over Na₂SO₄, filtered andconcentrated. The crude product was dissolved in dioxane (500 mL), andwater was added (250 mL). A 1N NaOH solution was added until the pHreached ˜10 (200 mL). The mixture was stirred for 1 hour and thenquenched with 1N KHSO₄ (250 mL). The mixture was extracted with EtOAc(3×250 mL) and the combined organic phases were washed with saturatedaqueous NaHCO₃, dried over Na₂CO₃, filtered and concentrated to a whitepaste. The paste was then slurried in 50% Et₂O/hexanes (200 mL) andfiltered through qualitative paper. The resulting white solid was washedwith 50% Et₂O/hexanes (3×200 mL) and the filtrate was concentrated. Thecrude residue was purified by column chromatography (10 to 40%Acetone/hexanes) to provide the product (22.4 g, 89%) as a thickcolorless oil.

Step C: Preparation of cis-tert-butyl4-fluoro-5-(4-nitrophenylsulfonyloxy)azepane-1-carboxylate:cis-tert-butyl 4-fluoro-5-hydroxyazepane-1-carboxylate (22.3 g, 95.59mmol) was dissolved in CH₂Cl₂ (240 mL). The solution was cooled to 0°C., 4-nitrobenzene-1-sulfonyl chloride (25.42 g, 114.7 mmol) was addedand the mixture was stirred for 30 minutes. NEt₃ (19.99 mL, 143.4 mmol)was added and the mixture was slowly warmed to ambient temperature over2 hours and stirred overnight. The mixture was diluted with CH₂Cl₂ andwashed with 1N KHSO₄ (2×100 mL) followed by washing with saturatedaqueous NaHCO₃ (100 mL) and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated. The crude orange solid was dissolvedin minimal hot CH₂Cl₂ and hexanes were added with stirring until thesolution became persistently cloudy. The warm mixture was cooled toambient temperature and allowed to stand undisturbed for 1 hour. Thesolids were collected by filtration and the solid was successivelywashed with hexanes followed by 50% Et₂O/hexanes and finally withhexanes again to provide the clean cis isomer of the product as a paleyellow solid (27.05 g, 68%).

Step D: Preparation of trans-tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yloxy)-5-fluoroazepane-1-carboxylate:cis-tert-butyl4-fluoro-5-(4-nitrophenylsulfonyloxy)azepane-1-carboxylate (0.484 g,1.16 mmol) and2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-ol (0.300 g,1.07 mmol) were slurried in CH₃CN (5.0 mL). To this mixture was added2-tert-butyl-1,1,3,3-tetramethylguanidine (0.259 mL, 1.28 mmol)dropwise. The dark solution was warmed to 40° C. and stirred overnight.The mixture was cooled to ambient temperature and diluted with water (10mL) and stirred for 15 minutes, then filtered. The solid was washed withwater and hexanes and dried in vacuo. The product was purified viacolumn chromatography (10 to 50% Acetone/CH₂Cl₂) to provide the productas off-white solid. MS ESI (+) m/z 496.0 (M+1) detected.

Step E: Isolation of Enantiomer 2 of trans-tert-butyl4-(2-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yloxy)-5-fluoroazepane-1-carboxylate:Racemic trans tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yloxy)-5-fluoroazepane-1-carboxylate was separated by chiral HPLC on a Prep Chiral OJ-Hcolumn using the following solvent system: 20% EtOH and 80% hexanes, toprovide the two enantiomers as peak 1 (9.715 minutes) and peak 2 (14.265minutes). Peak 2 was isolated to provide the title compound with 98% eeand 99% de.

Step F: Enantiomer 2 oftrans-2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro-8-5-fluoroazepan-4-yloxy)quinoline:Enantiomer 2 of trans-tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yloxy)-5-fluoroazepane-1-carboxylate(0.210 g, 0.424 mmol) was dissolved in CHCl₃ (4.3 mL). To this solutionwas added HCl (4.24 mL, 17.0 mmol, 4.0M Dioxane) and the mixture wasstirred at ambient temperature for 3 hours. The mixture was filteredthrough a polypropylene filter and washed with CH₂Cl₂ and Et₂O, thenslurried in hexanes and dried in vacuo to provide the desired product aswhite solid. MS ESI (+) m/z 396.1 (M+1) detected. Specific rotation:[α]²⁵ _(D)=−77° (c=0.95, MeOH).

Example 92

Enantiomer 1 ofcis-8-5-fluoroazepan-4-yloxy)-2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline

Step A: Preparation of 2-hydrazinyl-4-methylpyridine:2-Chloro-4-methylpyridine (3.43 mL, 39.19 mmol) and hydrazine hydrate(19.07 mL, 391.9 mmol) were suspended together in a flask and heated to150° C. for 72 hours. The mixture was concentrated in vacuo to an oil.The oil was taken up in EtOAc and the resulting solid was removed byvacuum filtration. The organic filtrate was washed with 40% aqueous NaOH(2×50 mL) and dried over Na₂SO₄, filtered and concentrated to providethe desired product (2.42 g, 54%) as a white solid.

Step B: Preparation of(E)-8-(tert-butyldimethylsilyloxy)-2-((2-(4-methylpyridin-2-yl)hydrazono)methyl)quinoline:2-Hydrazinyl-4-methylpyridine (0.280 g, 2.27 mmol) and8-(tert-butyldimethylsilyloxy)quinoline-2-carbaldehyde (0.653 g, 2.27mmol) were suspended in EtOH (6 mL) and stirred overnight at ambienttemperature. The resulting suspension was filtered and the solid waswashed with cold EtOH and dried in vacuo to provide the title compound(0.720 g; 81%).

Step C: Preparation of8-(tert-butyldimethylsilyloxy)-2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline:(E)-8-(tert-Butyldimethylsilyloxy)-2-((2-(4-methylpyridin-2-yl)hydrazono)methyl)quinoline(0.720 g, 1.83 mmol) was suspended in DCM (6 mL) at ambient temperature.Iodobenzene diacetate (0.650 g, 2.02 mmol) was added and the solutionwas allowed to stir at ambient temperature overnight. The mixture wasconcentrated to an orange oil and purified directly by columnchromatography (20% EtOAc/DCM to 50% EtOAc/DCM) to provide the desiredproduct (0.590 g, 82%).

Step D: Preparation of247-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol.8-(tert-butyldimethylsilyloxy)-2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline(0.580 g, 1.49 mmol) was suspended in THF (2 mL) and the solution wascooled to 0° C. Tetrabutylammonium fluoride hydrate (0.582 g, 2.23 mmol)was added to the solution and the mixture stirred at 0° C. for 10minutes, then warmed to ambient temperature and stirred for 4 hours. Themixture was diluted with a saturated aqueous NH₄Cl solution and EtOAc.The resulting white solid was isolated by vacuum filtration and wascombined with the organic layer which was concentrated. The solid thusobtained was slurried in H₂O for 10 minutes and the solids isolated byvacuum filtration and dried to provide the title compound (0.320 g, 78%)as a white solid. MS ESI (+) m/z 277.1 (M+1) detected.

Step E: Preparation of cis-tert-butyl4-fluoro-5-(2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)azepane-1-carboxylate:2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol (300 mg,1.09 mmol) was suspended in CH₃CN (5 mL) at ambient temperature, andtrans-tert-butyl4-fluoro-5-(4-nitrophenylsulfonyloxy)azepane-1-carboxylate (454 mg, 1.09mmol) and 2-tert-butyl-1,1,3,3-tetramethylguanidine (263 μL, 1.30 mmol)were added. The dark solution was stirred at 40° C. overnight, thenconcentrated to a grey solid which was slurried in water for 10 minutes.The solid was filtered, washed and dried in vacuo to provide the desiredproduct. MS ESI (+) m/z 492.3 (M+1) detected.

Step F: Isolation of Enantiomer 1 of cis-tert-butyl4-fluoro-5-(2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)azepane-1-carboxylate:Racemic cis-tert-butyl4-fluoro-5-(2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)azepane-1-carboxylatewas separated by chiral HPLC on a Prep Chiral OJ-H column using thefollowing solvent system: 90% hexanes, 10% EtOH, to provide the twoenantiomers as peak 1 (7.397 minutes) and peak 2 (10.335 minutes). Peak1 was collected to provide the title compound with 99% ee, 99% de.

Step G: Enantiomer 1 ofcis-8-5-fluoroazepan-4-yloxy)-2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline:Enantiomer 1 of cis-tert-butyl4-fluoro-5-(2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)azepane-1-carboxylate(0.161 g, 0.328 mmol) was dissolved in CHCl₃ (3 mL). To this solutionwas added HCl (6.55 mL, 13.1 mmol, 2.0M Et₂O) and the mixture wasstirred at ambient temperature for 4 hours. The mixture was filteredthrough a polypropylene filter, washed with CH₂Cl₂ and Et₂O, slurried inhexanes, then dried carefully in vacuo to provide the desired product asa white solid. MS ESI (+) m/z 392.1 (M+1) detected. Specific rotation:[α]²⁵ _(D)=−50° (c=1.0, MeOH).

Example 93

2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(3,3-difluoropiperidin-4-yloxy)-6-fluoroquinolinedihydrochloride

Step 1A: Preparation of N-(2,4-difluorophenyl)cinnamamide:2,4-difluoroaniline (9.0 g, 69.71 mmol) and pyridine (5.6 mL, 69.71mmol) were dissolved in dichloromethane (45 mL) and the solution wascooled to 0° C. A solution of cinnamoyl chloride (13.04 g, 76.7 mmol)dissolved in dichloromethane (45 mL) was added dropwise, and after theaddition the reaction was warmed to ambient temperature and stirred for16 hours. The reaction was quenched with saturated NaHCO₃ and the layerswere separated. The organic layer was washed with 1 M HCl then driedover Na₂SO₄ and concentrated in vacuo to provide a white solid. Thesolid was slurried in dichloromethane (150 mL), stirred for 30 minutes,and then hexanes (150 mL) were added. After stirring several minutes,the white solids were collected by filtration, washed withdichloromethane and air-dried to provide 13.5 g of the desired product.MS APCI (−) m/z 258.0 (M−1) detected.

Step 1B: Preparation of 6,8-difluoroquinolin-2-ol: SolidN-(2,4-difluorophenyl)cinnamamide (13.2 g, 50.7 mmol) was pre-mixed withaluminum trichloride (20.29 g, 152.2 mmol) and the mixture was heated to160° C. under gently flowing nitrogen gas for 80 minutes. The reactionwas cooled and quenched with ice, and the resultant beige solid wascollected by filtration, washed with water and air-dried to a light tansolid (9.89 g).

Step 1C: Preparation of 2-chloro-6,8-difluoro quinoline: 6,8-Difluoroquinolin-2-ol (9.89 g, 54.6 mmol) was slurried in 1,2-dichloroethane(550 mL) and treated with DMF (1 mL), and then 2M oxalyl chloride inCH₂Cl₂ (81.9 mL, 164 mmol) was added dropwise. The reaction was heatedto 70° C. for 1 hour and then cooled and concentrated in vacuo. Theresidue was dissolved in CHCl₃ and washed with 50% saturated NaHCO₃. Theaqueous layer (pH 8) was washed twice with CHCl₃ and the combinedorganics were dried over Na₂SO₄ and charcoal, filtered, and concentratedin vacuo to a brown solid. The solid was purified by recrystallizationfrom hot hexanes and 1,2-dichloroethane (minimum volume). The solid wascollected, washed with hexanes and air-dried to provide the desiredproduct as an off-white solid (5.78 g).

Step 2: Preparation of [1,2,4]triazolo[4,3-a]pyridine:2-Hydrazinylpyridine (5.06 g, 46.4 mmol) was treated withtriethoxymethane (50.2 mL, 302 mmol) and the mixture was heated toreflux for 4 hours with nitrogen flowing over the top of the aircondenser. The air condenser was replaced with a small distillation headand the low boiling solvents (75-80° C.) were removed from the system.Heating continued for 16 hours. The reaction was cooled to ambienttemperature and concentrated in vacuo to a dark residue. The residue waschromatographed on SiO₂ eluting with a gradient of 6% NH₄OH inMeOH/ethyl acetate. The desired product was isolated as a light orangesolid (4.2 g). MS APCI (+) m/z 120.0 (M+1) detected.

Step 3: Preparation of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6,8-difluoroquinoline:2-Chloro-6,8-difluoroquinoline (0.025 g, 0.125 mmol) was combined with[1,2,4]triazolo[4,3-a]pyridine (0.016 g, 0.14 mmol), micronized Cs₂CO₃(0.082 g, 0.25 mmol), and PdCl₂(PPh₃)₂ (0.0088 g, 0.013 mmol), and thesolids were slurried in dioxane (1.25 mL). The reaction was degassedwith argon (bubbled through the solution) then heated to reflux for 20hours. The crude reaction mixture was chromatographed without workup onSiO₂ eluting with a gradient of 6% NH₄OH in MeOH/ethyl acetate toprovide the desired product as an orange solid (21 mg).

Step 4A: Preparation of 1-benzyl-3,3-difluoropiperidine-4,4-diol: Ethyl1-benzyl-5,5-difluoro-4-oxopiperidine-3-carboxylate (6.00 g, 20.2 mmol;prepared as described in WO 2005/040120, p. 30) was dissolved in 3N HCl(60 mL) and heated to reflux for 16 hours. The reaction was cooled,adjusted to pH 8 with solid NaHCO₃, then extracted three times withethyl acetate. The combined organics were washed with saturated NaCl,dried over Na₂SO₄ and concentrated in vacuo to a white solid (5.1 g). MSAPCI (+) m/z 244.0 (M+1) detected.

Step 4B: Preparation of tert-butyl3,3-difluoro-4,4-dihydroxypiperidine-1-carboxylate:1-Benzyl-3,3-difluoropiperidine-4,4-diol (2.05 g, 8.43 mmol) wasdissolved in 95% EtOH (40 mL) and treated with di-tert-butyl dicarbonate(3.68 g, 16.9 mmol) and 10% Pd on carbon (Degeussa type, 200 mg). Thereaction was placed under a balloon of hydrogen gas and stirred for 12hours. The reaction mixture was filtered through a nylon membrane,washed with ethanol and concentrated in vacuo to a colorless oil (4.05g).

Step 4C: Preparation of tert-butyl3,3-difluoro-4-hydroxypiperidine-1-carboxylate: tert-Butyl3,3-difluoro-4,4-dihydroxypiperidine-1-carboxylate (3.10 g, 12.2 mmol)was dissolved in 95% EtOH (50 mL) and the solution was treated withsodium borohydride (2.32 g, 61.2 mmol) and stirred at ambienttemperature for 3 hours. The reaction was treated dropwise with 3N HCluntil vigorous gas evolution ceased, then stirred at ambient temperaturefor 20 minutes (pH of the mixture was 3-4 at this point). The reactionwas neutralized with saturated NaHCO₃ and concentrated in vacuo. Theresidue was dissolved in ethyl acetate and water and the layers wereseparated. The aqueous layer was washed with ethyl acetate and thecombined organic layers were washed with saturated NaCl, dried overNa₂SO₄ and concentrated in vacuo to provide the desired product as awhite solid (1.39 g).

Step 5A: Preparation of tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yloxy)-3,3-difluoropiperidine-1-carboxylate:tert-Butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate (0.0706 g,0.298 mmol) was treated with 1 M KOtBu in THF (0.283 mL, 0.283 mmol) andstirred for 15 minutes. The solution was treated with2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6,8-difluoroquinoline (0.042 g,0.149 mmol) and DMF (0.80 mL) then the mixture was stirred at ambienttemperature for 16 hours. The mixture was directly chromatographed onSiO₂ eluting with a gradient of 2% NH₄OH in isopropanol/ethyl acetate.The desired product was collected and concentrated to a colorless oil,(72 mg). MS APCI (+) m/z 500.0 (M+1) detected.

Step 5B: Preparation of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(3,3-difluoropiperidin-4-yloxy)-6-fluoroquinolinedihydrochloride salt: tert-Butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yloxy)-3,3-difluoropiperidine-1-carboxylate(0.072 g, 0.144 mmol) was dissolved in MeOH (0.72 mL) and treated with4.0 M HCl in dioxane (0.360 mL, 1.44 mmol), then stirred at ambienttemperature for 2 hours. The reaction mixture was concentrated in vacuo.The residue was taken up in MeOH and concentrated three times. Theresidue was chromatographed on SiO₂ eluting with a gradient of 2% NH₄OHin isopropanol/methylene chloride. The desired product was dissolved inMeOH (2 mL), treated with 2.0 M HCl in ether (0.809 mL, 1.62 mmol) andconcentrated in vacuo. The residue was again dissolve in MeOH andconcentrated in vacuo several times, then placed under vacuum to givethe desired product as a white solid (27.8 mg). MS APCI (+) m/z 400.3(M+1) detected.

Example 94

Enantiomer 1 of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((cis)-3-fluoropiperidin-4-yloxy)quinolinedihydrochloride

Step 1A: Preparation of N-(2-fluorophenyl)cinnamamide: Cinnamoylchloride (89.2 g, 535 mmol) was dissolved in THF (170 mL) and addeddropwise to a 0° C. solution of 2-fluoroaniline (54.1 g, 486 mmol) andpyridine (39.35 mL, 486.5 mmol) dissolved in THF (170 mL). The mixturewas allowed to warm to ambient temperature after the addition andstirred for 15 hours. A solution of 2M HCl was added (1250 mL) and themixture was stirred at ambient temperature for 8 hours, during which theinitial oil solidified to a light pink solid. This material wascollected by filtration, washed with several portions of water, andair-dried to provide the desired product (119.5 g).

Step 1B: Preparation of 8-fluoroquinolin-2-ol:N-(2-Fluorophenyl)cinnamamide (97.2 g, 403 mmol) was combined with AlCl₃(161 g, 1209 mmol) and the solids were thoroughly mixed. The dry mixturewas heated to 160° C. for 100 minutes. The reaction was cooled andquenched by addition of ice. A beige solid formed after completedispersion of the dark solids and this was stirred overnight. The beigesolid was filtered and air-dried overnight to provide the desiredproduct as a free-flowing solid (69.8 g).

Step 1C: Preparation of 2-chloro-8-fluoroquinoline:8-Fluoroquinolin-2-ol (35 g, 215 mmol) was slurried in1,2-dichloroethane (875 mL) and treated with DMF (3 mL) then a solutionof oxalyl chloride (2M in CH₂Cl₂) (322 mL, 644 mmol) was added dropwise.After the addition, the reaction was heated to 70° C. for 1 hour thencooled and concentrated in vacuo. The residue was dissolved in CHCl₃ andwashed with 50% saturated NaHCO₃. The aqueous layer (pH 8) was washedtwice with CHCl₃ and the combined organics were dried over Na₂SO₄,filtered and concentrated in vacuo to a brown solid (about 52 g). Thiscrude solid was dissolved in methylene chloride and filtered through aplug of SiO₂ eluting with methylene chloride. The desired material wasisolated as a light orange solid (32.9 g).

Step 2: Preparation of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-fluoroquinoline: 2-Chloro-8-fluoroquinoline (0.75 g, 4.13 mmol) was combinedwith [1,2,4]triazolo[4,3-a]pyridine (0.541 g, 4.54 mmol), micronizedCs₂CO₃ (2.69 g, 8.26 mmol), and PdCl₂(PPh₃)₂ (0.290 g, 0.413 mmol) thenthe mixture was slurried in dioxane (20 mL). The reaction wasdeoxygenated with argon and heated to reflux for 20 hours, then cooled,diluted with CHCl₃ and filtered through a pad of Celite®. The filtratewas concentrated onto Na₂SO₄ powder (15 g) and the mixture waschromatographed on SiO₂ eluting with a stepped gradient of 0-2%MeOH/ethyl acetate. The desired product was isolated as a cream-coloredsolid (1.12 g). MS APCI (+) m/z 265.3 (M+1) detected.

Step 3A: Preparation of benzyl4-(trimethylsilyloxy)-5,6-dihydropyridine-1(2H)-carboxylate: To benzyl4-oxopiperidine-1-carboxylate (152 g, 650 mmol) in DMF (650 mL) wasadded TMS-Cl (148 mL, 117 mmol) followed by triethylamine (326 mL, 234mmol). The slurry was warmed to 80° C. for 16 hours, diluted withhexanes (1 L), washed 3 times with saturated NaHCO₃ solution, dried overNa₂SO₄, filtered and concentrated to obtain benzyl4-(trimethylsilyloxy)-5,6-dihydropyridine-1(2H)-carboxylate, (199 g, 652mmol) as a orange oil.

Step 3B: Preparation of benzyl 3-fluoro-4-oxopiperidine-1-carboxylate:Selectfluor® (181.2 g, 511.4 mmol) was added portion-wise (about 25 gportions) to a ice cold solution of benzyl4-(trimethylsilyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (142 g, 465mmol) in CH₃CN (2 L) over approximately 30 minutes. The ice bath wasremoved and the mixture was allowed to stand for 12 hours. The mixturewas concentrated to a slurry, diluted with EtOAc and brine and thelayers were separated. The brine phase was extracted once with EtOAc,and the combined organic phases were washed with saturated NaHCO₃ andbrine, dried over Na₂SO₄, filtered and concentrated in vacuo to providethe desired product as a dark thick oil (112 g).

Step 3C: Preparation of cis-benzyl3-fluoro-4-hydroxypiperidine-1-carboxylate: L-Selectride® (663 mL, 663mmol) was added dropwise to an ice cold solution of benzyl3-fluoro-4-oxopiperidine-1-carboxylate (138.9 g, 552.8 mmol) dissolvedin anhydrous THF (421 mL). The ice bath was removed and the reaction wasallowed to stand for 12 hours. The reaction mixture was carefully added(dropwise, via addition funnel) to a vigorously stirring mixture of 80mL MeOH, 2 N NaOH (1400 mL) H₂O₂ (376 mL, 50%) in a large amount of ice,taking care to control the temperature rise. The mixture was stirred for12 hours, then 2 L of EtOAc was added. The mixture was stirred anadditional 1 hour. The layers were separated and the aqueous phase wasextracted with EtOAc. The combined organic phases were dried overNa₂SO₄, filtered and concentrated in vacuo to an oil (112 g). Theresidue was purified by flash column chromatography (silica gel, elutingwith a gradient of 30% EtOAc to 75% EtOAc in hexanes) to afford 38 g ofthe desired compound.

Step 3D: Preparation of non-racemic cis-benzyl3-fluoro-4-hydroxypiperidine-1-carboxylate: A 32 g sample of thematerial of Step 3C was separated by chiral SFC separation (3 cm×15 cmChiralpak AD-H column; mobile phase 22% Ethanol/CO₂, 100 bar; flow rate100 mL/min; 50 mg/mL injections, 1.5 mL injection volume; 220 nM) toafford first eluting peak (Peak 1; 11.2 g, Rt 2.63 min) in >99% ee andsecond eluting peak (Peak 2; 11.8 g, Rt 4.01 min) in >99% ee.

Step 4A: Preparation of Enantiomer 1 of (cis)-benzyl4-(2-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-3-fluoropiperidine-1-carboxylate:Non-racemic (cis)-benzyl 3-fluoro-4-hydroxypiperidine-1-carboxylate(Peak 1 of Example 94, Step 3D; 0.288 g, 1.14 mmol) was treated with 1.0M KOtBu in THF (1.10 mL, 1.10 mmol) and stirred at ambient temperaturefor 15 minutes. 2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-8-fluoroquinoline(0.200 g, 0.757 mmol) was added as a solid, followed by the addition ofDMF (3.3 mL), and the resultant mixture was stirred at ambienttemperature for 40 hours. The crude reaction mixture was chromatographedon SiO₂ eluting with a gradient of (2% NH₄OH in isopropanol)/methylenechloride. The desired product was isolated as a pale yellow solid (196mg). MS APCI (+) m/z 498.2 (M+1) detected.

Step 4B: Preparation of Enantiomer 1 of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((cis)-3-fluoropiperidin-4-yloxy)quinoline:Enantiomer 1 of (cis)-benzyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-3-fluoropiperidine-1-carboxylate(0.185 g, 0.372 mmol) was dissolved in dioxane (4.6 mL) and treated with6 M hydrogen chloride (4.65 mL, 27.9 mmol) and the reaction mixture washeated at 100° C. for 2 hours. The reaction was cooled and carefullyneutralized with solid NaHCO₃. The resulting aqueous layer (pH 8-9) wasextracted four times with methylene chloride and the resulting organiclayers were combined and dried over Na₂SO₄ then concentrated in vacuo.The residue was chromatographed on SiO₂ eluting with a gradient of 6%NH₄OH in MeOH)/methylene chloride. The desired material was isolated asa colorless film (22 mg). MS APCI (+) m/z 364.1 (M+1) detected.

Step 4C: Preparation of the dihydrochloride salt of Enantiomer 1 of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((cis)-3-fluoropiperidin-4-yloxy)quinoline:Non-racemic2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((cis)-3-fluoropiperidin-4-yloxy)quinoline(20 mg, 0.055 mmol) was dissolved in MeOH (2 mL) and treated with 4M HClin dioxane (1 mL, 4 mmol). The mixture was stirred for 5 minutes thenconcentrated in vacuo. The residue was dissolved in fresh MeOH andconcentrated in vacuo three times to a pale yellow solid (20.7 mg, 86%).Specific rotation: [α]²⁰ _(D)+26° (c=0.45, 1:1 water/95% ethanol).

Example 95

Enantiomer 2 of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((cis)-3-fluoropiperidin-4-yloxy)quinolinedihydrochloride

Step 1: Preparation of Enantiomer 2 of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((cis)-3-fluoropiperidin-4-yloxy)quinoline:Prepared according to the method of Example 94 using Peak 2 ofnon-racemic (cis)-benzyl 3-fluoro-4-hydroxypiperidine-1-carboxylate(Example 94, Step 3D) in place of Peak 1 of non-racemic (cis)-benzyl3-fluoro-4-hydroxypiperidine-1-carboxylate (Example 94, Step 3D) in step4A. MS APCI (+) m/z 364.1 (M+1) detected.

Step 2: Preparation of the dihydrochloride salt Enantiomer 2 of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((cis)-3-fluoropiperidin-4-yloxy)quinoline:Prepared as described in Example 94 using non-racemic2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((cis)-3-fluoropiperidin-4-yloxy)quinolinein Step 4C. Specific rotation: [α]²⁰ _(D)-48° (c=0.46, 1:1 water/95%ethanol).

Example 96

Enantiomer 1 of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((trans)-3-fluoropiperidin-4-yloxy)quinolinedihydrochloride

Step 1A: Preparation of Enantiomer 1 of (trans)-benzyl4-(benzoyloxy)-3-fluoropiperidine-1-carboxylate: Non-racemic(cis)-benzyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (Peak 1 ofExample 94, Step 3D; 0.306 g, 1.21 mmol) was treated withtriphenylphosphine (0.475 g, 1.81 mmol) and benzoic acid (0.221 g, 1.81mmol) and the solids were dissolved in THF (5 mL), then cooled to 0° C.The solution was treated dropwise with diisopropyl azodicarboxylate(0.357 mL, 1.81 mmol) dissolved in THF (1 mL). The solution was warmedto ambient temperature with a bath and stirred for 7 days, thenconcentrated in vacuo. The residue was dissolved in CH₂Cl₂ and washedwith saturated NH₄Cl, water, 50% saturated NaHCO₃, dried over Na₂SO₄ andconcentrated in vacuo to a colorless oil. The oil was chromatographed onSiO₂ eluting with 1:12 acetone/hexanes. The desired fraction wasisolated to provide the desired product as a colorless oil (385 mg).

Step 1B: Preparation of Enantiomer 1 of (trans)-benzyl3-fluoro-4-hydroxypiperidine-1-carboxylate: Enantiomer 1 of(trans)-benzyl 4-(benzoyloxy)-3-fluoropiperidine-1-carboxylate (6.50 g,18.2 mmol) was dissolved in THF/MeOH/water (2:2:1, 50 mL) and treatedwith lithium hydroxide hydrate (1.53 g, 36.4 mmol), and the reaction wasstirred at 50° C. for 2 hours. The reaction mixture was cooled, quenchedwith saturated NH₄Cl to pH 8, concentrated in vacuo and the aqueouslayer (pH 8) was extracted with methylene chloride. The combined organiclayer was dried over Na₂SO₄ and concentrated in vacuo to a colorless oil(295 mg). The crude material was chromatographed on SiO₂ eluting with2:1 hexanes/ethyl acetate. The desired material was isolated as acolorless oil (3.7 g).

Step 2A: Preparation of Enantiomer 1 of (trans)-benzyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-3-fluoropiperidine-1-carboxylate:Non-racemic (trans)-benzyl 3-fluoro-4-hydroxypiperidine-1-carboxylate(0.192 g, 0.757 mmol) was treated with 1.0 M KOtBu in THF (0.757 mL,0.757 mmol) and stirred at ambient temperature for 15 minutes.2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-8-fluoro quinoline (0.200 g,0.757 mmol) was added along with DMF (2.25 mL) and the mixture wasstirred at 50° C. for 15 hours. The reaction was cooled andchromatographed on SiO₂, eluting with a gradient of 2% NH₄OH inisopropanol/methylene chloride. After concentration in vacuo, thedesired product was isolated as a beige solid (0.306 g). MS APCI (+) m/z498.1 (M+1) detected.

Step 2B: Preparation of Enantiomer 1 of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((trans)-3-fluoropiperidin-4-yloxy)quinoline:Non-racemic (trans)-benzyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-3-fluoropiperidine-1-carboxylate(0.304 g, 0.611 mmol) was dissolved in dioxane (7.6 mL) and treated with6 M hydrogen chloride (7.64 mL, 45.8 mmol), and the reaction mixture washeated at 100° C. for 15 hours. The reaction was cooled and carefullyneutralized with solid NaHCO₃. Additional water was added to dissolvethe resulting NaCl as the neutralization proceeded. The resultingaqueous layer (pH 8-9) was extracted with methylene chloride and thecombined organic layers were dried over Na₂SO₄ and concentrated invacuo. The crude product was chromatographed on SiO₂ eluting with agradient of 2% NH₄OH in isopropanol/methylene chloride. The desiredproduct was isolated as a white foam (62.6 mg). MS APCI (+) m/z 364.2(M+1) detected.

Step 2C: Preparation of the dihydrochloride salt of Enantiomer 1 of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((trans)-3-fluoropiperidin-4-yloxy)quinoline:Prepared as described in Example 94 using non-racemic2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((trans)-3-fluoropiperidin-4-yloxy)quinolinein Step 4C. Specific rotation: 0.45, 1:1 water/95% ethanol).

Example 97

Enantiomer 2 of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((trans)-3-fluoropiperidin-4-yloxy)quinolinedihydrochloride

Step 1: Preparation of Enantiomer 2 of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((trans)-3-fluoropiperidin-4-yloxy)quinoline:Prepared according to the method of Example 96 using Peak 2 ofnon-racemic (cis)-benzyl 3-fluoro-4-hydroxypiperidine-1-carboxylate(Example 94, Step 3D) in place of Peak 1 non-racemic (cis)-benzyl3-fluoro-4-hydroxypiperidine-1-carboxylate (Example 94, Step 3D) in step1A. MS APCI (+) m/z 364.1 (M+1) detected.

Step 2: Preparation of the dihydrochloride salt of Enantiomer 2 of 2-k[1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((trans)-3-fluoropiperidin-4-yloxy)quinoline:Prepared as described in Example 94 using non-racemic2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((trans)-3-fluoropiperidin-4-yloxy)quinolinein Step 4C. Specific rotation: [α]²⁰ _(D)+2.7° (c=0.45, 1:1 water/95%ethanol).

Example 98

2-(6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((trans)-5-fluoroazepan-4-yloxy)quinolinedihydrochloride

Step A: Preparation of2-(6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol:Prepared according to the method of Example 64, Steps A-B. MS APCI (+)m/z 303 (M+1) detected.

Step B: Preparation of trans-tert-butyl4-(2-(6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-5-fluoroazepane-1-carboxylate:Prepared according to the method of Example 90 using cis-tert-butyl4-fluoro-5-(4-nitrophenylsulfonyloxy)azepane-1-carboxylate in place oftrans-tert-butyl4-fluoro-5-(4-nitrophenylsulfonyloxy)azepane-1-carboxylate and2-(6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol inplace of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-ol inStep C and running the reaction at 50° C.

Step C: Preparation of2-(6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((trans)-5-fluorozepan-4-yloxy)quinolinedihydrochloride: To a solution of trans-tert-butyl4-(2-(6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-5-fluoroazepane-1-carboxylate(0.076 g, 0.147 mmol) in 1.5 mL DCM was added neat trifluoroacetic acid(0.339 mL, 4.40 mmol). The reaction mixture was stirred at ambienttemperature for 90 minutes, then concentrated twice from DCM and driedin vacuo. The crude was dissolved in DCM, and a few drops oftriethylamine and a few drops MeOH were added. The crude material wasthen purified by preparative TLC (eluting first with 9:1 DCM:6% NH₄OH inMeOH, then with 4:1 DCM:6% NH₄OH in MeOH). The product band wasisolated, and the isolated material was dissolved in 1 mL DCM and a fewdrops of MeOH. This solution was added dropwise to a vigorously stirringsolution of 1 mL 2M HCl/ether in 15 mL ether, causing a precipitate toform. The solids were isolated by filtration through a medium glassfritted funnel by pushing the solvent through with nitrogen pressure,rinsed with ether, dried under nitrogen pressure, and dried in vacuo togive the desired product as the dihydrochloride salt (0.036 g, 50.0%yield) as a white powder. MS APCI (+) m/z 418 (M+1) detected.

Example 99

Enantiomer 1 of8-((trans)-5-fluoroazepan-4-yloxy)-2-(6-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolinedihydrochloride

Step A: Preparation of (trans)-tert-butyl4-(2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-5-fluoroazepane-1-carboxylate.Prepared according to the method of Example 98, using2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol in place of2-(6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol inStep A.

Step B: Preparation of enantiomer 1 of (trans)-tert-butyl4-fluoro-5-(2-(6-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)azepane-1-carboxylate. To a solution of (trans)-tert-butyl4-(2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-5-fluoroazepane-1-carboxylate(0.125 g, 0.225 mmol) and Pd(PPh₃)₄ (0.0519 g, 0.0449 mmol) in 1.9 mLTHF was added 2M methyl zinc chloride in THF (0.225 mL, 0.449 mmol) bysyringe, and the reaction mixture was heated in an 80° C. reactionblock. After 6 hours, the reaction mixture was cooled to ambienttemperature and saturated NH₄Cl and water were added, causing aprecipitate to form. The solids were isolated by vacuum filtrationthrough qualitative filter paper, rinsed with water, air dried, anddried in vacuo. The crude was purified on silica gel (1-8% MeOH in DCMgradient) to give the racemic (trans)-product. The resulting mixture wasseparated by chiral HPLC using a Chiracell OJ-H column, 9.5% EtOH inhexanes, flow rate 16 mL/min to give Peak 1 trans-product (0.018 g, 16%,99% ee) as a white solid, and Peak 2 trans-product (0.014 g, 13%, 92%ee) as a white solid.

Step C: Preparation of enantiomer 1 of8-((trans)-5-fluoroazepan-4-yloxy)-2-(6-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolinedihydrochloride. To a solution of Peak 1 trans-product from Step C(0.018 g, 0.0366 mmol) in 0.8 mL DCM was added neat trifluoroacetic acid(0.141 mL, 1.83 mmol). The reaction mixture was stirred at ambienttemperature for 2 hours, then concentrated to dryness and dried invacuo. The resulting residue was dissolved in 1.5 mL DCM and severaldrops MeOH, and this solution was added to a vigorously stirringsolution of 1 mL 2M HCl/ether in 10 mL ether, causing a precipitate toform. The mixture was stirred 5 minutes, then concentrated to drynessand dried in vacuo. The solids were dissolved in 1 mL DCM and severaldrops MeOH, and this solution was added dropwise to a vigorouslystirring solution of 10 mL ether, causing precipitation. The solids wereisolated by filtration through a 0.2 micron nylon filter membrane bypushing the solvent through with nitrogen pressure, rinsed with ether,1:1 ether/DCM, and again with ether, dried under nitrogen pressure, anddried in vacuo to give the corresponding trans-enantiomer 1 as thedihydrochloride salt (0.013 g, 76.5% yield) as a pale yellow powder. MSAPCI (+) m/z 392 (M+1) detected.

Example 100

Enantiomer 2 of8-((trans)-5-fluoroazepan-4-yloxy)-2-(6-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline

Prepared according to the method of Example 99 using Peak 2trans-product (from Step C) in place of Peak 1 trans-product in Step C.APCI (+) m/z 392 (M+1) detected.

Example 101

3-(8-((trans)-5-fluoroazepan-4-yloxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitriledihydrochloride

Step A: Preparation of3-(8-(tert-butyldimethylsilyloxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile.Prepared according to the method of Example 98, Steps B-C, using5-cyano-2-hydrazinylpyridine in place of 2-hydrazinylpyridine in Step B.

Step B: Preparation of3-(8-hydroxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile.Prepared according to the method of Example 64, using3-(8-(tert-butyldimethylsilyloxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrilein place of8-(tert-butyldimethylsilyloxy)-2-(6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolinein Step B and rinsing the crude product with water, ethyl acetate, andether.

Step C: Preparation of (trans)-tert-butyl4-(2-(6-cyano-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-5-fluoroazepane-1-carboxylate.Prepared according to the method of Example 90, using cis-tert-butyl4-fluoro-5-(4-nitrophenylsulfonyloxy)azepane-1-carboxylate in place oftrans-tert-butyl4-fluoro-5-(4-nitrophenylsulfonyloxy)azepane-1-carboxylate and3-(8-hydroxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrilein place of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-olin Step C and running the reaction at 50° C.

Step D: Preparation of3-(8-((trans)-5-fluoroazepan-4-yloxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitriledihydrochloride. Prepared according to the method of Example 99 using(trans)-tert-butyl4-(2-(6-cyano-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-5-fluoroazepane-1-carboxylatein place of Peak 1 trans-enantiomer in Step C to give the title compoundas the dihydrochloride salt. MS APCI (+) m/z 403 (M+1) detected.

Example 102

2-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((trans)-5-fluoroazepan-4-yloxy)quinolinedihydrochloride

Prepared according to the method of Example 101, using5-fluoro-2-hydrazinylpyridine in place of 5-cyano-2-hydrazinylpyridinein Step A to give the title compound as the dihydrochloride salt. MSAPCI (+) m/z 396 (M+1) detected.

Example 103

2-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-fluoropiperidin-4-yl)methoxy)quinolinedihydrochloride

Prepared according to the method of Example 101 using5-fluoro-2-hydrazinylpyridine in place of 5-cyano-2-hydrazinylpyridinein Step A and (4-fluoropiperidin-4-yl)methyl methanesulfonate in placeof (cis)-tert-butyl4-fluoro-5-(4-nitrophenylsulfonyloxy)azepane-1-carboxylate in Step C togive the title compound as the dihydrochloride salt. MS APCI (+) m/z 396(M+1) detected.

Example 104

2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8((1-ethyl-4-fluoropiperidin-4-yl)methoxy)quinolinedihydrochloride

Prepared according to the method of Example 84 using acetaldehyde inplace of 37% formaldehyde in water to give the title compound as thedihydrochloride salt. MS APCI (+) m/z 406 (M+1) detected.

Example 105

2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-fluoro-1-(2-fluoroethyl)piperidin-4-yl)methoxy)quinolinedihydrochloride

To a suspension of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-fluoropiperidin-4-yl)methoxy)quinolinedihydrochloride (Example 66; 0.070 g, 0.16 mmol) and1-bromo-2-fluoroethane (0.16 g, 1.24 mmol) in 0.8 mL DMF was added DIEA(0.11 mL, 0.62 mmol). The reaction mixture was stirred at 80° C. for 5days. The reaction mixture was concentrated, and the crude was purifiedtwice by preparative TLC (1 mm plate, 9:1 DCM:MeOH). The resultingresidue was dissolved in 0.8 mL DCM and added to a vigorously stirringsolution of 1.5 mL 2M HCl/ether in 30 mL ether, causing precipitation.The mixture was concentrated and dried in vacuo. The resulting solidswere dissolved in several drops MeOH and 1 mL DCM, and this solution wasadded to a vigorously stirring solution of ether, causing precipitation.The solids were isolated by filtration through a 0.2 micron nylon filterdisc by pushing solvent through the filter with nitrogen pressure,rinsed with ether, 1:1 ether/DCM, and again with ether, dried undernitrogen pressure, then dried in vacuo to give the desired product asthe dihydrochloride salt (0.020 g, 26% yield) as an off-white powder. MSAPCI (+) m/z 424 (M+1) detected.

Example 106

2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro-8-((4-fluoropiperidin-4-yl)methoxy)quinolinedihydrochloride

Prepared according to the method of Example 66 using2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-ol (Example39, Step F) in place of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol in Step C. MS APCI(+) m/z 396 (M+1) detected.

Example 107

2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((3-fluoroazetidin-3-yl)methoxy)quinolinedihydrochloride

Step A: Preparation of tert-butyl 3-oxoazetidine-1-carboxylate. To a−78° C. solution of 2M oxalyl chloride (31.8 mL, 63.5 mmol) in 200 mLDCM was added DMSO (9.01 mL, 127 mmol), followed by the slow addition byaddition funnel of a solution of tert-butyl3-hydroxyazetidine-1-carboxylate (10.0 g, 57.7 mmol) in 200 mL DCM. Thecloudy reaction mixture was stirred at −78° C. for 15 minutes, then asolution triethylamine (32.2 mL, 231 mmol) in 40 mL DCM was added slowlyby addition funnel. The reaction mixture was stirred another 15 minutes,the bath was removed, and the reaction was allowed to warm to ambienttemperature and stirred for 15 hours. Water and brine were added, andthe mixture was extracted with DCM. The combined extracts were dried(Na₂SO₄), filtered and concentrated. The crude was purified on silicagel (3-20% ethyl acetate in hexanes gradient) to give the desiredproduct (9.0 g, 91.1% yield) as a white solid.

Step B: Preparation of tert-butyl 3-methyleneazetidine-1-carboxylate. Toa 0° C. mixture of KOtBu (5.90 g, 52.6 mmol) in 95 mL ether was addedmethyltriphenylphosphonium bromide (18.8 g, 52.6 mmol). The reactionmixture was warmed to ambient temperature and stirred 1.5 hours. Asolution of tert-butyl 3-oxoazetidine-1-carboxylate (4.50 g, 26.3 mmol)in 10 mL ether was added. The reaction mixture was heated to reflux for2 hours, then cooled to ambient temperature. Solids were removed byvacuum filtration through compressed Celite and rinsed with ether, andthe filtrate was concentrated. The resulting residue was suspended in1:1 hexanes:ethyl acetate, and the solids were removed by vacuumfiltration through GF/F paper and rinsed with 1:1 hexanes:ethyl acetate.The filtrate was concentrated, and the resulting oil was purified onsilica gel (5-20% ethyl acetate in hexanes gradient) to give the desiredproduct (3.50 g, 78.7% yield) as a clear colorless oil.

Step C: Preparation of tert-butyl1-oxa-5-azaspiro[2.3]hexane-5-carboxylate. To a 0° C. solution oftert-butyl 3-methyleneazetidine-1-carboxylate (3.50 g, 20.7 mmol) in 115ml, CHCl₃ was added 77% mCPBA (13.9 g, 62.0 mmol) in 3 batches.Isopropyl alcohol (2 mL) was added. The reaction mixture was stirred for10 minutes, then warmed to ambient temperature and stirred. After 19hours, the milky reaction mixture was cooled to 0° C., 10 mL isopropylalcohol was added (reaction mixture clarified), and another 1 equivalentof mCPBA was added. The reaction mixture was warmed to ambienttemperature and stirred 2 hours, then another 1 equivalent mCPBA wasadded portionwise. After a total of 40 hours, the reaction mixture wascooled to 0° C., and 200 mL of 1:1 saturated Na₂S₂O₃/saturated NaHCO₃was added slowly by pouring portionwise through ice (internaltemperature was monitored; an initial 10° C. exotherm was observed). Themixture was stirred for 30 minutes, then extracted with CHCl₃, andcombined extracts were dried (Na₂SO₄), filtered, and concentrated. Thecrude was purified on silica gel (5-50% ethyl acetate in hexanesgradient) to give the desired product (1.0 g, 26.1% yield) as a clearcolorless oil.

Step D: Preparation of tert-butyl3-42-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-3-hydroxyazetidine-1-carboxylate.Prepared according to the method of Example 66 using tert-butyl1-oxa-5-azaspiro[2.3]hexane-5-carboxylate in place of tert-butyl4-fluoro-4-((methylsulfonyloxy)methyl)piperidine-1-carboxylate in Step Cand running the reaction at 70° C.

Step E: Preparation of tert-butyl3-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-3-fluoroazetidine-1-carboxylate.(NOTE: the reaction was run in a 10 mL plastic bottle) To a 0° C. cloudysolution of tert-butyl3-42-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-3-hydroxyazetidine-1-carboxylate(0.070 g, 0.156 mmol) in 2 mL DCM was added Deoxo-Fluor (0.0346 mL,0.188 mmol). The reaction mixture was warmed to ambient temperature, andafter 30 minutes, it was cooled back to 0° C., and another 2 equiv. ofDeoxoFluor was added, and the reaction mixture continued to stir at 0°C. After a total of 3.5 hours, saturated NaHCO₃ was carefully addeddropwise until the excess Deoxofluor was quenched. The mixture wasextracted with DCM, and the combined extracts were dried (Na₂SO₄),filtered, and concentrated. The residue was purified by preparative TLC(2 mm plate, 9:1 DCM:MeOH) to give the desired product (0.0156 g, 22.2%yield) as a white foam.

Step F: Preparation of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((3-fluoroazetidin-3-yl)methoxy)quinolinedihydrochloride. To a solution of tert-butyl3-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-3-fluoroazetidine-1-carboxylate(0.016 g, 0.0356 mmol) in 1 mL DCM was added neat trifluoroacetic acid(0.137 mL, 1.78 mmol). The reaction mixture was stirred at ambienttemperature for 1 hour, after which it was concentrated. The crude waspurified on C18 reverse phase (10-40% acetonitrile in water gradient).The resulting solids were dissolved in 1 mL DCM plus several drops MeOH,and this solution was added to a vigorously stirring solution of 1 mL 2MHCl/ether in 15 mL ether, causing precipitation. The mixture was stirredfor 5 minutes, then concentrated to dryness and dried in vacuo. Thesolids were dissolved in minimal MeOH/DCM, and this solution was addeddropwise to 20 mL vigorously stirring ether, causing precipitation. Thewhite solids were isolated by filtration through a 0.2 micron nylonfilter disc by pushing solvent through with nitrogen pressure, rinsedwith ether, dried under nitrogen pressure, and dried in vacuo to givethe title compound as the dihydrochloride salt (0.002 g, 13%) as a whitepowder. MS APCI (+) m/z 350 (M+1) detected.

Example 108

2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro-8-((3-fluoroazetidin-3-yl)methoxy)quinoline Dihydrochloride

Prepared as described for Example 107 using2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-ol (Example39, Step F) in place of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol in Step D. MS APCI(+) m/z 368 (M+1) detected.

Example 109

8((4-fluoropiperidin-4-yl)methoxy)-2-(6-methoxy-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolinedihydrochloride

Step A: Preparation of 2-hydrazinyl-5-methoxypyridine.2-bromo-5-methoxypyridine (4.90 g, 26.06 mmol) and anhydrous hydrazine(8.179 mL, 260.6 mmol) were combined and heated slowly to 140° C. in asand bath and stirred for 24 hours. The reaction mixture was dilutedwith THF and concentrated three times. The resulting solids weresuspended in 20 mL THF, stirred vigorously, and 100 mL ether was added.The resulting solids were cooled in a refrigerator for 2 hours, thenisolated by filtration through a 0.4 micron nylon filter disc withnitrogen pressure, rinsed with ether, 1:1 ether:ethyl acetate, andether, and dried in vacuo to give the desired product (>100%).

Step B: Preparation of2-(6-methoxy-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol. Preparedas described for Example 1, Steps A-D, using2-hydrazinyl-5-methoxypyridine in place of 2-hydrazinylpyridine in StepB.

Step C: Preparation of8-((4-fluoropiperidin-4-yl)methoxy)-2-(6-methoxy-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolinedihydrochloride. Prepared according to the method of Example 66, StepsC-D, using 2-(6-methoxy-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-olin place of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol in StepC to give the desired product. MS APCI (+) m/z 408 (M+1) detected.

Example 110

6-fluoro-8-((4-fluoropiperidin-4-yl)methoxy)-2-(6-methoxy-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolinedihydrochloride

Prepared as described for Example 109 using6-fluoro-2-(6-methoxy-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol(Example 39, Step F) in place of2-(6-methoxy-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol in Step C.MS APCI (+) m/z 426 (M+1) detected.

Example 111

8((4-fluoropiperidin-4-yl)methoxy)-2-(7-(2-methoxyethoxy)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolinedihydrochloride

Step A: Preparation of 2-fluoro-5-(2-methoxyethoxy)pyridine. To a 0° C.suspension of Cs₂CO₃ (18.73 g, 57.48 mmol) in 150 mL DMF was added6-fluoropyridin-3-ol (5.0 g, 44.21 mmol). The cloudy brown mixture wasstirred for 15 minutes, then 1-bromo-2-methoxyethane (6.232 mL, 66.32mmol) was added. The reaction mixture was heated in a 110° C. sand bathand stirred for 17 hours, after which it was cooled to ambienttemperature and the DMF was removed in vacuo. The resulting residue wascombined with saturated NH₄Cl and the mixture was extracted with DCM.The combined extracts were dried (Na₂SO₄), filtered, and concentrated.The crude material was purified on silica gel (5-50% ethyl acetate inhexanes gradient) to give the desired product (7.00 g, 92.50% yield) asa clear, colorless oil.

Step B: Preparation of8-((4-fluoropiperidin-4-yl)methoxy)-2-(7-(2-methoxyethoxy)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolinedihydrochloride. Prepared as described for Example 109 using2-fluoro-5-(2-methoxyethoxy)pyridine in place of2-bromo-5-methoxypyridine in Step A to give the desired product as thedihydrochloride salt. MS APCI (+) m/z 452 (M+1) detected.

Example 112

(R)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yloxy)-3,3-dimethylbutane-1,2-dioldihydrochloride

Step A: Preparation of (R)-3,3-dimethylbutane-1,2,4-triol:(R)-3-hydroxy-4,4-dimethyldihydrofuran-2(3H)-one (3.21 g, 24.7 mmol) wasadded to 30 mL THF and cooled to 0° C. Lithium aluminum hydride (24.7mL, 24.7 mmol) was added slowly and the reaction was warmed to ambienttemperature and heated for 6 hours at reflux, during which aheterogeneous mixture of white solids formed. The reaction was cooled toambient temperature, and 1 mL water was added, followed by the additionof 1 mL of a 15% NaOH aqueous solution (w/v) and 3 mL of water, and thereaction was stirred overnight. The reaction was passed through Celiteand filtered, rinsed with copious amounts of ethyl acetate, then driedover Na₂SO₄. The mixture was filtered, the filtrate was concentrated,and excess water was azeotroped with toluene-DCM (1-1). The residue wasdried under high vacuum for 1 hour to yield 2.4 g of the desired productas a clear thick oil.

Step B: Preparation of(R)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropan-1-ol:(R)-3,3-dimethylbutane-1,2,4-triol (2.7 g, 20 mmol) and4-methylbenzenesulfonic acid (0.017 g, 0.10 mmol) were added to 25 mL ofacetone and catalytic 4-methylbenzenesulfonic acid (0.017 g, 0.10 mmol)and stirred overnight at ambient temperature. The solution wasevaporated, and to the residue was added ethyl acetate. The organiclayer was washed with aqueous Na₂CO₃, dried over MgSO₄ and filtered. Thefiltrate was concentrated to provide 1.7 g of the desired product as aclear oil.

Step C: Preparation of(R)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropyl4-nitrobenzenesulfonate:(R)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropan-1-ol (0.823 g,4.72 mmol) was added to 10 mL of DCM and cooled to 0° C. Triethylamine(0.982 mL, 7.09 mmol) and hypochlorous 4-nitrobenzenesulfonic anhydride(1.35 g, 5.67 mmol) were added and the solution was warmed to ambienttemperature and stirred overnight. The solids were filtered off, and thefiltrate was evaporated. The residue was purified on silica gel usinghexane and ethyl acetate to yield 0.9 g of the desired product as a darkbeige solid.

Step D: Preparation of(R)-2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropoxy)-6-fluoroquinoline: 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-ol(0.09 g, 0.34 mmol),(R)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropyl methanesulfonate(0.11 g, 0.45 mmol) and cesium carbonate (0.22 g, 0.69 mmol) were addedto 1 to 2 mL of DMA and heated to 85° C. for 4-5 hours. The reaction wasconcentrated and treated with water and ethyl acetate. The reaction wasextracted several times with ethyl acetate. The organic layer was driedover MgSO₄, filtered, and concentrated. The residue was purified onSilica gel using 2% NH₄OH in isopropyl acetate and DCM to provide 200mgs of the desired product (85% pure).

Step E: Preparation of(R)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yloxy)-3,3-dimethylbutane-1,2-dioldihydro chloride:(R)-2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropoxy)-6-fluoroquinoline(0.190 g, 0.435 mmol) was added to methanol saturated with HCl andstirred for 30 minutes. The solution was evaporated, DCM was added, andthe material triturated and filtered to yield 140 mgs of the desiredproduct as orange solid. MS ESI (+) m/z 397 (M+1) detected.

Example 113

(R)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-3,3-dimethylbutane-1,2-diol

Step A: Preparation of(R)-2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropoxy)quinoline:2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol (0.25 g, 0.95 mmol),(R)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropyl4-nitrobenzenesulfonate (0.41 g, 1.1 mmol) and cesium carbonate (0.62 g,1.9 mmol) were added to minimal amount of N,N-dimethylacetamide andheated to 85° C. The reaction was cooled, ethyl acetate was added andthe mixture was sonicated. Solids were filtered off and the filtrate wasdried over MgSO₄, filtered and evaporated. The crude material waspurified on silica gel using isopropyl alcohol containing 2% NH₄OH andDCM to yield 30 mg of the desired product (90% pure. The crude materialwas used without further purification in the next step.

Step B: Preparation of(R)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-3,3-dimethylbutane-1,2-diol:(R)-2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropoxy)quinoline(0.030 g, 0.072 mmol) was added to 1 N HCl in methanol and stirred for30 minutes, then evaporated, co-evaporated once in methanol andtriturated in DCM to isolate 23 mg of 95% pure desired product as abeige solid. MS ESI (+) m/z 379 (M+1) detected.

Example 114

2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro-8-((4-methoxyazepan-4-yl)methoxy)quinolinebis-trifluoroacetate

Step A: Preparation of tert-butyl4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-4-hydroxyazepane-1-carboxylate:2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-ol (0.065 g,0.25 mmol), cesium carbonate (0.16 g, 0.50 mmol) and tert-butyl1-oxa-6-azaspiro[2.6]nonane-6-carboxylate (0.068 g, 0.30 mmol) wereadded to 1 mL of DMF and heated to 72° C. overnight. The reactionmixture was concentrated, and DCM was added to the residue. Solids wereremoved by filtration and the filtrate was purified on Silica gel using6% NH₄OH in MeOH and DCM to yield 74 mg of the desired product as anoff-white foam. MS ESI (+) m/z 490 (M+1) detected.

Step B: Preparation of tert-butyl4-42-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yloxy)methyl)-4-methoxyazepane-1-carboxylate:tert-butyl4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yloxy)methyl)-4-hydroxyazepane-1-carboxylate(0.060 g, 0.106 mmol) and sodium hydride (0.00468 g, 0.117 mmol) wereadded to 1 mL of DMF, then iodomethane (0.00732 mL, 0.117 mmol) wasadded and the reaction stirred for 1 hour at ambient temperature. Thereaction mixture was concentrated, and DCM was added to the residue.Solids were removed by filtration and the filtrate was purified onSilica gel using 6% NH₄OH in MeOH and DCM to yield 32 mg of the desiredproduct as a clear oil. MS ESI (+) m/z 522 (M+1) detected.

Step C: Preparation of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro-8-((4-methoxyazepan-4-yl)methoxy)quinoline:tert-butyl4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yloxy)methyl)-4-methoxyazepane-1-carboxylate(0.032 g, 0.061 mmol) was added to a mixture of trifluoroacetic acid andDCM (1:1) for 1 hour. The reaction was concentrated and co-evaporatedseveral times with diethyl ether to yield 32 mgs of the desired productas a white solid. MS ESI (+) m/z 422 (M+1) detected.

Example 115

2-(4-42-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yloxy)methyl)-4-methoxyazepan-1-yl)ethanoldihydrochloride

The free base of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro-8-((4-methoxyazepan-4-yl)methoxy)quinoline(prepared as described in Example 114, Step C) (0.006 g, 0.0142 mmol)was taken up in DMA and 2-bromoethanol (0.00402 mL, 0.0569 mmol) andN-isopropyl-N-methylpropan-2-amine (0.00899 mL, 0.0569 mmol) were added.The reaction mixture was stirred for 1 hour at 75° C., then cooled,evaporated, co-evaporated with DCM. HCl in diethyl ether was added, andthe resulting solids were isolated and dried to yield 6 mg of thedesired product as the dihydrochloride salt. MS ESI (+) m/z 466 (M+1)detected.

Example 116

4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)azepan-4-olbis-trifluoroacetate

Step A: Preparation of tert-butyl4-42-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-4-hydroxyazepane-1-carboxylate:2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol (0.09 g, 0.34 mmol),tert-butyl 1-oxa-6-azaspiro[2.6]nonane-6-carboxylate (0.086 g, 0.38mmol) and cesium carbonate (0.22 g, 0.69 mmol) were added to 1 mL of DMAin a sealed vial and heated to 70° C. overnight. The reaction wasconcentrated, and the residue was purified on Silica gel using 6% NH₄OHin MeOH and CHCl₃ to yield 56 mgs of 70% pure desired product(contaminated with starting phenol). MS ESI (+) m/z 490 (M+1) detected.

Step B: Preparation of4-42-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)azepan-4-ol:tert-Butyl4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-4-hydroxyazepane-1-carboxylate(0.0039 g, 0.0080 mmol) was treated with a mixture of trifluoroaceticacid and DCM (1:1) for 1 hour. The reaction was concentrated to provide4 mgs of the desired material as a solid. MS ESI (+) m/z 390 (M+1)detected.

Example 117

2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-methoxyazepan-4-yl)methoxy)quinolinedihydrochloride

Step A: Preparation of tert-butyl4-42-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-4-hydroxyazepane-1-carboxylate:Prepared according to the procedure described in Example 116, Step A.

Step B: Preparation of tert-butyl4-42-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-4-methoxyazepane-1-carboxylate:tert-Butyl4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-4-hydroxyazepane-1-carboxylate(0.056 g, 0.114 mmol), iodomethane (0.00858 mL, 0.137 mmol) and sodiumhydride (0.00915 g, 0.229 mmol) were added to DMF (1 mL) at ambienttemperature and stirred for 2 hours. The reaction was concentrated andthe residue was purified on Silica gel using methanol (containing 6%NH₄OH) and DCM, to yield 39 mg of the desired product (67% pure). MS ESI(+) m/z 504 (M+1) detected.

Step C: Preparation of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((4-methoxyazepan-4-yl)methoxy)quinoline:tert-Butyl4-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-4-methoxyazepane-1-carboxylate(0.040 g, 0.079 mmol) was added to a mixture of trifluoroacetic acid andDCM (1:1) for 30 minutes, and the reaction was concentrated. Ethylacetate was added and the suspension was filtered through a Watersfilter (to remove any errant silica gel), and the filtrate wasconcentrated. DCM was added followed by precipitation with HCl dissolvedin diethyl ether, evaporated, co-evaporated in diethyl ether to yield 16mgs of the desired product as a yellow solid (95% pure by LC). MS ESI(+) m/z 404 (M+1) detected.

Example 118

Stereoisomers 1 and 2 of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((trans)-5-fluoro-1-methylazepan-4-yloxy)quinoline

Step A: Preparation of Stereoisomers 1 and 2 of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((5-fluoroazepan-4-yloxy)quinoline:A mixture of cis and trans tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-5-fluoroazepane-1-carboxylatewas prepared according to Example 46, Step E. The crude material waspurified by column chromatography (Biotage SP1, 340G SNAP, 15% to 60%EtOAc/hexanes), and the first eluting material was collected to providea racemic mixture of the Stereoisomers 1 and 2 as a thick colorless oilwhich slowly became a white solid.

Step B: Preparation of Stereoisomers 1 and 2 of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((trans)-5-fluoro-1-methylazepan-4-yloxy)quinoline:A mixture of Stereoisomers 1 and 2 of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((trans)-5-fluoroazepan-4-yloxy)quinoline(0.023 g, 0.0511 mmol) was slurried in CH₂Cl₂ (3 mL). A saturatedaqueous Na₂CO₃ solution (5 mL) was added and the mixture was stirred atambient temperature for 0.5 hours. The layers were separated and theaqueous phase was extracted with CH₂Cl₂. The combined organic layerswere washed with brine and dried over Na₂SO₄, filtered and concentrated.The crude residue was treated with formic acid (0.289 mL, 7.66 mmol) andformaldehyde (0.0380 mL, 0.511 mmol). The mixture was stirred at 90° C.for 4 hours. The mixture was cooled to ambient temperature and carefullytreated with a saturated aqueous Na₂CO₃ solution to adjust the mixtureto about pH 11. The mixture was extracted with CHCl₃ and the combinedorganic phases were washed with brine and dried over Na₂SO₄, filteredand concentrated. The crude product was purified by Preparative TLC (0.5mm, 10% MeOH/CH₂Cl₂ with 1% 7N NH₃/MeOH) to provide the desired product(0.011 g, 55%) as a white solid. MS ESI (+) m/z 392.1 (M+1) detected.

Example 119

Stereoisomers 3 and 4 of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-5-fluoro-1-methylazepan-4-yloxy)quinoline

Step A: Preparation of Stereoisomers 3 and 4 of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((5-fluoroazepan-4-yloxy)quinoline:A mixture of cis and trans tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-5-fluoroazepane-1-carboxylatewas prepared according to Example 46, Step E. The crude material waspurified by column chromatography (Biotage SP1, 340G SNAP, 15% to 60%EtOAc/hexanes), and the second eluting material was collected to providea racemic mixture of the Stereoisomers 3 and 4 of isomers as a thickcolorless oil which slowly became a white solid.

Step B: Preparation of Stereoisomers 3 and 4 of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-5-fluoro-1-methylazepan-4-yloxy)quinoline:A mixture of Stereoisomers 3 and 4 of tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-5-fluoroazepane-1-carboxylate(0.021 g, 0.0440 mmol) was dissolved in formic acid (0.332 mL, 8.80mmol). Formaldehyde (0.0327 mL, 0.440 mmol, 37% aqueous) was added, andthe mixture was stirred at 90° C. for 4 hours. The mixture was cooled toambient temperature and treated with a saturated aqueous Na₂CO₃ solutionto adjust the mixture to about pH 11. The mixture was extracted withCHCl₃ and the combined organic phases were washed with brine and driedover Na₂SO₄, filtered and concentrated. The crude product was purifiedby Preparative TLC (0.5 mm, 10% MeOH/CH₂Cl₂ with 1% 7N NH₃/MeOH) toprovide the desired product (0.016 g, 93%) as a white solid. MS ESI (+)m/z 392.1 (M+1) detected.

Example 120

Enantiomer 2 of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro-8-((cis)-5-fluoroazepan-4-yloxy)quinoline

Enantiomer 2 of (cis)-tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yloxy)-5-fluoroazepane-1-carboxylate(Example 90, Step D; 0.119 g, 0.240 mmol) was dissolved in CHCl₃ (2.4mL). HCl (2.40 mL, 9.61 mmol, 4.0M Dioxane) was added and the mixturewas stirred at ambient temperature for 3 hours. The mixture was filteredthrough a polypropylene filter and washed with CH₂Cl₂ and then Et₂O,then slurried in hexanes and dried carefully in vacuo to provide 0.095 gof the desired product as a white solid (85%). MS ESI (+) m/z 396.1(M+1) detected.

Example 121

2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro-8-(trans-5-fluoroazepan-4-yloxy)quinoline

Enantiomer 1 of trans-tert-butyl4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yloxy)-5-fluoroazepane-1-carboxylate(Peak 1 from Example 91, Step E; 0.210 g, 0.424 mmol) was dissolved inCHCl₃ (4.3 mL). To this solution was added HCl (4.24 mL, 17.0 mmol, 4.0MDioxane) and the mixture was stirred at ambient temperature for 3 hours.The mixture was filtered through a polypropylene filter and washed withCH₂Cl₂ and Et₂O, slurried in hexanes and then dried carefully in vacuoto provide the desired product as white solid. MS ESI (+) m/z 396.1(M+1) detected.

Example 122

8-((cis-4,5)-5-fluoroazepan-4-yloxy)-2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline

Enantiomer 2 of cis-tert-butyl4-fluoro-5-(2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)azepane-1-carboxylate(Peak 2 from Example 92, Step F; 0.161 g, 0.328 mmol) was dissolved inCHCl₃ (3 mL). To this solution was added HCl (6.55 mL, 13.1 mmol, 2.0MEt₂O) and the mixture was stirred at ambient temperature for 4 hours.The mixture was then filtered through a polypropylene filter and washedwith CH₂Cl₂ and then Et₂O and finally slurried in hexanes then driedcarefully in vacuo to provide the desired product as a white solid. MSESI (+) m/z 392.1 (M+1) detected.

Example 123

2,2-dimethyl-3-(2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)propan-1-aminetrihydrochloride

Step A: Preparation of(E/Z)-8-(tert-butyldimethylsilyloxy)-2-((2-(4-methylpyridin-2-yl)hydrazono)methyl)quinoline:A mixture of 8-(tert-butyldimethylsilyloxy)quinoline-2-carbaldehyde(6.11 g, 21.3 mmol) and 2-hydrazinyl-4-methylpyridine (2.62 g, 21.3mmol) in ethanol (60 mL) was stirred at ambient temperature overnight.The resulting precipitate was filtered, washed with cold ethanol anddried in vacuo to provide 5.92 g (71%) of desired product as abeige-colored solid.

Step B: Preparation of8-(tert-butyldimethylsilyloxy)-2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline:To a suspension of(E/Z)-8-(tert-butyldimethylsilyloxy)-2-42-(4-methylpyridin-2-yl)hydrazono)methyl)quinoline(5.92 g, 15.1 mmol) in dichloromethane (50 mL) was added iodosobenzenediacetate (5.34 g, 16.6 mmol). The mixture was stirred at ambienttemperature overnight and then concentrated under reduced pressure. Theresidue was purified by silica gel chromatography eluting with 1:4 ethylacetate/hexanes followed by 1:2 ethyl acetate/hexanes to provide 5.00 g(85%) of desired product.

Step C: Preparation of2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol: To asolution of8-(tert-butyldimethylsilyloxy)-2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline(5.00 g, 12.8 mmol) in tetrahydrofuran (100 mL) at 0° C. was addedtetrabutylammonium fluoride (19.2 mL, 1 M in tetrahydrofuran, 19.2mmol). The reaction was stirred for 6 hours at ambient temperature andthen diluted with saturated aqueous ammonium chloride. The mixture wasconcentrated under reduced pressure, triturated with water, filtered andair-dried to provide 3.50 g (99%) of desired product as a white solid.

Step D: Preparation of tert-butyl2,2-dimethyl-3-(2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)propylcarbamate:A mixture of2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol (preparedaccording to Example 1; 50 mg, 0.18 mmol),3-(tert-butoxycarbonylamino)-2,2-dimethylpropyl methanesulfonate (102mg, 0.36 mmol) and cesium carbonate (118 mg, 0.36 mmol) indimethylacetamide (2 mL) was heated to 50° C. overnight. The mixture wasconcentrated under reduced pressure and purified by successive silicagel chromatography, eluting with 1:9 methanol/dichloromethane and agradient of dichloromethane to 1:9 methanol/dichloromethane. The residuewas then purified by preparative thin layer chromatography eluting with3:7 acetone/dichloromethane to provide 35 mg (42%) of desired product asa light yellow solid.

Step E: Preparation of2,2-dimethyl-3-(2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)propan-1-aminetrihydrochloride: A mixture of tert-butyl2,2-dimethyl-3-(2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)propylcarbamate(35 mg, 0.076 mmol) and hydrochloric acid (4 M in dioxane, 0.57 mL, 2.3mmol) in dichloromethane (0.5 mL) was stirred overnight. The reactionwas concentrated under reduced pressure. The residue was evaporated fromtwice from toluene, once from hexanes, triturated with hexanes, filteredand dried in vacuo to provide 25 mg (70%) of desired product as thetrihydrochloride salt. MS ESI (+) m/z 362 (M+1) detected.

Example 124

2-(7-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((3R,4S)-3-fluoropiperidin-4-yloxy)quinoline

Prepared according to the method of Example 123 using4-chloro-2-hydrazinylpyridine in place of 2-hydrazinyl-4-methylpyridinein Step A and(3R,4R)-tert-butyl-3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylatein place of 3-(tert-butoxycarbonylamino)-2,2-dimethylpropylmethanesulfonate in Step D. MS ESI (+) m/z 398 (M+1) detected.

Example 125

8((4-methoxypiperidin-4-yl)methoxy)-2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolinedi-trifluoroacetate

Step A: Preparation of tert-butyl4-hydroxy-4-42-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)piperidine-1-carboxylate:A mixture of2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol (preparedaccording to Example 1; 20 mg, 0.72 mmol),tert-butyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate (178 mg, 0.83 mmol)and cesium carbonate (472 mg, 1.5 mmol) in dimethylacetamide (2.5 mL)was heated to 98° C. overnight. The mixture cooled to ambienttemperature, filtered through celite and concentrated under reducedpressure. The residue was purified by silica gel chromatography with agradient of dichloromethane to 1:9 methanol/dichloromethane to provide170 mg (48%) of desired product.

Step B: Preparation of tert-butyl4-methoxy-4-((2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)piperidine-1-carboxylate:A mixture of tert-butyl4-hydroxy-4-((2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)piperidine-1-carboxylate(50 mg, 0.10 mmol) and sodium hydride (18 mg, 0.82 mmol) indimethylformamide (1 mL) was stirred at ambient temperature for 15minutes. Iodomethane (0.051 mL, 0.82 mmol) was added and the solutionwas stirred at ambient temperature overnight. The reaction wasconcentrated under reduced pressure. The residue was dissolved indichloromethane and washed twice with saturated aqueous ammoniumcarbonate. The organic phase was dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was triturated withhexanes and further purified by preparative thin layer chromatographywith 1:9 methanol/dichloromethane to provide 25 mg (46%) of desiredproduct.

Step C: Preparation of8-((4-methoxypiperidin-4-yl)methoxy)-2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolinedi-trifluoroacetate: A mixture of tert-butyl4-methoxy-4-((2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)piperidine-1-carboxylate(30 mg, 0.060 mmol) and trifluoroacetic acid (0.37 mL, 4.8 mmol) indichloromethane (1 mL) was at ambient temperature for 30 minutes. Thereaction was concentrated under reduced pressure. The residue wastriturated with diethyl ether, filtered and dried in vacuo to provide 12mg (52%) of desired product as the di-trifluoroacetate salt. MS ESI (+)m/z 404 (M+1) detected.

Example 126

242-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)morpholine

Prepared according to the method of Example 16 using tert-butyl2-(hydroxymethyl)morpholine-4-carboxylate in place of tert-butyl3-(hydroxymethyl)piperidine-1-carboxylate. MS ESI (+) m/z 362.1 (M+1)detected.

Example 127

Enantiomer 1 of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(azepan-4-yloxy)quinoline

Prepared according to the procedure of Example 90, using2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(azepan-4-yloxy)quinoline(Example 52) as the starting material.Racemic-2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(azepan-4-yloxy)quinoline-1-carboxylatewas separated by chiral HPLC on a Prep Chiral OJ-H column using thefollowing solvent mixture: 75% heptane, 20% EtOH, 3% MeOH, 2%acetonitrile, to provide the enantiomers as peak 1 (7.32 minutes) andpeak 2 (8.54 minutes). Peak 1 was isolated to provide the title compound99% ee. MS ESI (+) m/z 360.1 (M+1) detected.

Example 128

Enantiomer 2 of2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(azepan-4-yloxy)quinoline

Prepared according to the procedure of Example 90, using2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(azepan-4-yloxy)quinoline(Example 52) as the starting material.Racemic-2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(azepan-4-yloxy)quinoline-1-carboxylatewas separated by chiral HPLC on a Prep Chiral OJ-H column using thefollowing solvent mixture: 75% heptane, 20% EtOH, 3% MeOH, 2%acetonitrile, to provide the enantiomers as peak 1 (7.32 minutes) andpeak 2 (8.54 minutes). Peak 2 was isolated to provide the title compound98% ee. MS ESI (+) m/z 360.1 (M+1) detected.

Example 129

(1-((2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)cyclopentyl)methanamine

Prepared according to the method of Example 16 using tert-butyl(1-(hydroxymethyl)cyclopentyl)methylcarbamate in place of tert-butyl3-(hydroxymethyl)piperidine-1-carboxylate. MS ESI (+) m/z 374.5 (M+1)detected.

Example 130

2-42-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)butan-1-ol

Prepared according to the method of Example 22, using2-ethylpropane-1,3-diol in place of 1,1-bis(hydroxymethyl)cyclopropane.MS ESI (−) m/z 347.2 (M−1) detected.

Example 131

2-42-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)-2-ethylbutan-1-ol

Prepared according to the method of Example 22, using2,2-diethylpropane-1,3-diol in place of1,1-bis(hydroxymethyl)cyclopropane. MS ESI (−) m/z 377.2 (M+1) detected.

Example 132

4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-3,3-dimethylbutan-1-amine

Prepared according to the method of Example 18, using tert-butyl4-hydroxy-3,3-dimethylbutylcarbamate in place of tert-butyl3-hydroxy-2,2-dimethylpropylcarbamate.

MS ESI (+) m/z 362.3 (M+1) detected.

Example 133

2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-((3-fluoropiperidin-3-yl)methoxy)quinoline

Prepared according to the method of Example 16, using tert-butyl3-fluoro-3-(hydroxymethyl)piperidine-1-carboxylate in place of usingtert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate. MS ESI (+) m/z378.2 (M+1) detected.

Example 134

N-(3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethylpropyl)-2-fluoroacetamide

2-Fluoroacetyl chloride (12 mg, 0.13 mmol) was added to a stirredsolution of3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethylpropan-1-amine(prepared according to Example 18; 30 mg, 0.086 mmol) anddiisopropylethyl amine (45 μL, 0.26 mmol) in DCM (2 mL) at 0° C. After30 minutes, the reaction was quenched with saturated aqueous bicarbonate(5 mL), extracted into EtOAc, washed with water, dried over Na₂SO₄followed by concentration in vacuo. The resulting oil was purified byflash column chromatography (silica gel), eluting with 100% EtOAc(Biotage) to give the desired product (12 mg, 0.029 mmol, 34% yield) asa white solid. MS ESI (+) m/z 408.2 (M+1) detected.

Example 135

3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-N-(2,2-difluoroethyl)-2,2-dimethylpropan-1-aminehydrochloride

2,2-diFluoroethyl trifluoromethanesulfonate (17 μL, 0.13 mmol) was addedto a stirred solution of3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethylpropan-1-amine(30 g, 0.086 mmol) and diisopropylethyl amine (39 μt 0.22 mmol) in dryTHF/DMF (1 mL/1 mL) at ambient temperature. After stirring overnight,the reaction was diluted with EtOAc, washed with saturated aqueousbicarbonate, dried over Na₂SO₄, and concentrated in vacuo. The residuewas purified by flash column chromatography (silica gel), eluting with50% EtOAc/hexanes, affording the desired product (10 mg). MS ESI (+) m/z412.2 (M+1) detected.

Example 136

3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethyl-N-(2,2,2-trifluoroethyl)propan-1-amine

Prepared according to the method of Example 135, using2,2,2-trifluoroethyl trifluoromethanesulfonate in place of2,2-difluoroethyl trifluoromethanesulfonate. MS ESI (+) m/z 430.2 (M+1)detected.

1. A compound of general Formula I:

or a pharmaceutically acceptable salt thereof, wherein: A is OR¹⁰ orNR¹¹R¹²; B is H, F, Cl, OR^(a), (1-6C alkyl)NR^(b)R^(c), (1-6C alkyl)OH,CH(OH)CH₂OH, or (1-4C alkyl); R¹ is H, F, Cl, Br, Me, cyclopropyl or CN;R^(1a), R², R³ and R⁴ are independently H, F, Cl, Br, Me or CN; R⁵ andR⁷ are independently H, F, Me or CN; R⁶ is H, F, Me, Br, CN,cyclopropyl, phenyl, MeO— or MeOCH₂CH₂O—; R¹⁰ is H, hetCyc¹, -(1-3Calkyl)hetCyc^(1a), hetCyc², (CR¹⁷R¹⁸)_(p)(CR¹³R¹⁴)CH₂NR¹⁵R¹⁶,—(CR¹⁷R¹⁸)_(p)(CR¹³R¹⁴)CH₂OH, (1-6C alkyl), hetAr¹, (1-3Calkyl)hetAr^(1a), or (3-7C)cycloalkyl substituted with NH₂, NH(1-6Calkyl) or N(1-6C alkyl)₂; R¹¹ is H or (1-6C)alkyl; R¹² is hetCyc³, (1-6Calkyl)NR¹⁵R¹⁶, C(O)(1-6C alkyl)NR¹⁵R¹⁶, (1-6C alkyl)NHC(O)O(1-6C alkyl),or (4-7C)cycloalkyl optionally substituted with OH, NH₂, NH(1-6C alkyl)or N(1-6C alkyl)₂; R¹³ is H, (1-6C)alkyl, F or OH, and R¹⁴ is H,(1-6C)alkyl or F, or R¹³ and R¹⁴ together with the carbon atom to whichthey are attached form a 3-6 membered carbocyclic ring; each R¹⁵, R¹⁶,R¹⁷ and R¹⁸ is independently H or (1-6C)alkyl, or each R¹⁵, R¹⁷ and R¹⁸is independently H or (1-6C)alkyl and R¹⁶ is H, (1-6C)alkyl, C(═O)CH₂F,CH₂CHF₂ or CH₂CF₃; or NR¹⁵R¹⁶ forms a 5-6 membered heterocyclic ringhaving a first ring heteroatom which is N and optionally having a secondring heteroatom selected from N and O; hetCyc¹, hetCyc^(1a), and hetCyc³are independently a 4-7 membered heterocycle having a ring nitrogen atomand optionally substituted with one or more R⁹ groups, or hetCyc¹ andhetCyc³ are independently a 4-7 membered heterocycle having a ringnitrogen atom and optionally substituted with one or more R⁹ groups, andhetCyc^(1a) is selected from a morpholinyl and 4-7 membered azacyclicring optionally substituted with one or more R⁹ groups; each R⁹ isindependently selected from halogen, (1-6C)alkyl, cyclopropylmethyl,benzyl, NR^(f)R^(g), -(1-6C alkyl)NR^(h)R^(i), OR^(j), (1-6Calkyl)OR^(k), (1-6C)fluoroalkyl, C(O)NR^(m)R^(n), (1-6Calkyl)C(O)NR^(p)R^(q), and C(O)O(1-6C alkyl); hetCyc² is an 8-memberedbridged heterocycle having a ring nitrogen atom; hetAr¹ and hetAr^(1a)are independently a 5 or 6 membered heteroaryl having 1-2 ring nitrogenatoms and optionally substituted with one or more substituentsindependently selected from F, Cl, Br, Me, cyclopropyl, CN, NH₂, NH(1-6Calkyl) and N(1-6C alkyl)₂; R^(a) is H, (1-6C alkyl), -(1-6Calkyl)-O-(1-6C alkyl) or -(1-6C alkyl)-O-(3-6C cycloalkyl); each R^(b),R^(f), R^(g), R^(h), R^(i), R^(k), R^(m), R^(p) and R^(q) isindependently selected from H and (1-6C alkyl); R^(j) is H, (1-6C alkyl)or cyclopropyl; R^(n) is H, (1-6C alkyl), —O(1-6C alkyl) or —O(3-6Ccycloalkyl); and p is 0, 1 or
 2. 2. A compound of claim 1, wherein: A isOR¹⁰ or NR¹¹R¹²; B is H, F, OR^(a), (1-6C alkyl)NR^(b)R^(c), (1-6Calkyl)OH, CH(OH)CH₂OH or (1-4C alkyl); R¹ is H, F, Cl, Br, Me,cyclopropyl or CN; R^(1a), R², R³ and R⁴ are independently H, F, Cl, Br,Me or CN; R⁵ and R⁷ are independently H, F, Me or CN; R⁶ is H, F, Me,Br, CN, cyclopropyl or phenyl; R¹⁰ is H, hetCyc¹, -(1-3Calkyl)hetCyc^(1a), hetCyc², —(CR¹⁷R¹⁸)_(p)(CR¹³R¹⁴)CH₂NR¹⁵ R¹⁶,—(CR¹⁷R¹⁸)_(p)(CR¹³R¹⁴)CH₂OH, (1-6C alkyl), hetAr¹, (1-3Calkyl)hetAr^(1a), or (3-7C)cycloalkyl substituted with NH₂, NH(1-6Calkyl) or N(1-6C alkyl)₂; R¹¹ is H or (1-6C)alkyl; R¹² is hetCyc³, (1-6Calkyl)NR¹⁵R¹⁶, C(O)(1-6C alkyl)NR¹⁵R¹⁶, (1-6C alkyl)NHC(O)O(1-6C alkyl),or (4-7C)cycloalkyl optionally substituted with OH, NH₂, NH(1-6C alkyl)or N(1-6C alkyl)₂; R¹³ is H, (1-6C)alkyl, F or OH, and R¹⁴ is H,(1-6C)alkyl or F, or R¹³ and R¹⁴ together with the carbon atom to whichthey are attached form a 3-6 membered carbocyclic ring; each R¹⁵, R¹⁶,R¹⁷ and R¹⁸ is independently H or (1-6C)alkyl, or NR¹⁵R¹⁶ forms a 5-6membered heterocyclic ring having a first ring heteroatom which is N andoptionally having a second ring heteroatom selected from N and O;hetCyc¹, hetCyc^(1a), and hetCyc³ are independently a 4-7 memberedheterocycle having a ring nitrogen atom and optionally substituted withone or more R⁹ groups; each R⁹ is independently selected from halogen,(1-6C)alkyl, cyclopropylmethyl, benzyl, NR^(f)R^(g), -(1-6Calkyl)NR^(h)R^(i), OR^(j), (1-6C alkyl)OR^(k), (1-6C)fluoroalkyl,C(O)NR^(m)R^(n), (1-6C alkyl)C(O)NR^(p)R^(q), and C(O)O(1-6C alkyl);hetCyc² is an 8-membered bridged heterocycle having a ring nitrogenatom; hetAr¹ and hetAr^(1a) are independently a 5 or 6 memberedheteroaryl having 1-2 ring nitrogen atoms and optionally substitutedwith one or more substituents independently selected from F, Cl, Br, Me,cyclopropyl, CN, NH₂, NH(1-6C alkyl) and N(1-6C alkyl)₂; R^(a) is H,(1-6C alkyl), -(1-6C alkyl)-O-(1-6C alkyl) or -(1-6C alkyl)-O-(3-6Ccycloalkyl); each R^(b), R^(f), R^(g), R^(h), R^(i), R^(k), R^(m), R^(p)and R^(q) is independently selected from H and (1-6C alkyl); R^(j) is H,(1-6C alkyl) or cyclopropyl; R^(n) is H, (1-6C alkyl), —O(1-6C alkyl) or—O(3-6C cycloalkyl); and p is 0, 1 or
 2. 3. The compound of claim 1,where B is H, F, OR^(a), (1-6C alkyl)NR^(b)R^(c), (1-6C alkyl)OH, orCH(OH)CH₂OH.
 4. The compound of claim 1, wherein A is OR¹⁰.
 5. Thecompound of claim 4, wherein R¹⁰ is hetCyc¹, -(1-3Calkyl)hetCyc^(1a) orhetCyc², wherein hetCyc¹ and hetCyc^(1a) are optionally substituted withone or more R⁹ groups.
 6. The compound of claim 5, wherein each R⁹ isindependently selected from F, (1-6C)alkyl, C(O)O(1-6C)alkyl, (1-6Calkyl)OR^(k), C(O)N^(m)R^(n), (1-6C alkyl)C(O)NR^(p)R^(q), and OR^(j).7. The compound of claim 6, wherein hetCyc¹ and -(1-3C alkyl)hetCyc^(1a)are optionally substituted with one or two R⁹ groups independentlyselected from Me, Et, isopropyl, cyclopropylmethyl, F, OH, OMe, CH₂OH,CH₂CH₂OH, CH₂CH₂F, CH₂OMe, C(═O)OMe, C(═O)NH₂ and CH₂C(═O)NH₂.
 8. Thecompound of claim 4, wherein R¹⁰ is —(CR¹⁷R¹⁸)_(p)(CR¹³R¹⁴) CH₂NR¹⁵R¹⁶.9. The compound of claim 4, wherein R¹⁰ is —(CR¹⁷R¹⁸)_(p)(CR¹³R¹⁴)CH₂OH.10. The compound of claim 4, wherein R¹⁰is (1-6C alkyl).
 11. Thecompound of claim 4, wherein R¹⁰ is (3-7C)cycloalkyl substituted withNH₂, NH(1-6C alkyl) or N(1-6C alkyl)₂.
 12. The compound of claim 4,wherein R¹⁰ is hetAr¹ or (1-3C alkyl)hetAr^(1a).
 13. The compound ofclaim 1, wherein A is NR¹¹R¹².
 14. The compound of claim 13, wherein R¹²is hetCyc³ optionally substituted with one or more R⁹ groups.
 15. Thecompound of claim 14, wherein each R⁹ is independently selected from(1-6C) alkyl.
 16. The compound of claim 13, wherein R¹² is(4-7C)cycloalkyl optionally substituted with OH, NH₂, NH(1-6C alkyl) orN(1-6C alkyl)₂.
 17. The compound of claim 13, wherein R¹² is (1-6Calkyl)NR¹⁵R¹⁶, C(O)(1-6C alkyl)NR¹⁵R¹⁶ or (1-6 C alkyl)NHC(O)(1-6Calkyl).
 18. The compound of claim 1, wherein B is H.
 19. The compound ofclaim 1, wherein B is OR^(a).
 20. The compound of claim 19, wherein B isselected from OMe, —OCH₂CH₂OMe and —OCH₂CH₂O(cyclopropyl).
 21. Thecompound of claim 1 wherein B is F.
 22. The compound of claim 1, whereinB is (1-6C alkyl)NR^(b)R^(c).
 23. The compound of claim 1, wherein B is(1-6C alkyl)OH.
 24. The compound of claim 1, wherein B is CH(OH)CH₂OH.25. The compound of claim 1, wherein B is (1-4C alkyl).
 26. The compoundof claim 1, wherein B is Cl.
 27. The compound of claim 1, wherein eachof R¹, R², R³, R⁵ and R⁷ is hydrogen.
 28. A pharmaceutical composition,which comprises a compound of Formula I of claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable diluent or carrier.
 29. A compound of Formula I as defined inclaim 1, or a pharmaceutically acceptable salt thereof, for use in thetreatment of an inflammatory or autoimmune disease.
 30. A compound asdefined in claim 29, wherein the inflammatory or autoimmune disease ismultiple sclerosis, lupus or inflammatory bowel disease.
 31. A compoundof Formula I as defined in claim 1 or a pharmaceutically acceptable saltthereof, for use in the treatment of cancer.
 32. A method of treating aPIM-1 and/or PIM-2 and/or PIM-3 kinase-mediated condition in a mammal,which comprises administering to said mammal a therapeutically effectiveamount of a compound of Formula I as defined in claim 1, or apharmaceutically acceptable salt thereof.
 33. A method of treating aninflammatory or autoimmune disorder in a mammal, which comprisesadministering to said mammal a therapeutically effective amount of acompound of Formula I as defined in claim 1, or a pharmaceuticallyacceptable salt thereof.
 34. The method as defined in claim 33 whereinthe inflammatory or autoimmune disease is multiple sclerosis, lupus orinflammatory bowel disease.
 35. A method of treating cancer in a patientin need thereof, comprising administering to said patient a compound asdefined in claim 1, or a pharmaceutically acceptable salt thereof.
 36. Aprocess for the preparation a compound of claim 1, which comprises: (a)for a compound of Formula I wherein A is NR¹¹R¹², coupling acorresponding compound having the formula II

wherein L¹ represents a leaving atom or group, with a compound havingthe formula HNR¹¹R¹², using a palladium (II) catalyst and a ligand inthe presence of a base; or (b) reacting a compound of Formula III

with a compound having the Formula IV

in the presence of an organo hypervalent iodine reagent; or (c) for acompound of Formula I wherein A is OR¹⁰, coupling a correspondingcompound having the Formula V

with a compound having the formula HO—R¹⁰ in the presence of a couplingagent and triphenylphosphine in a suitable solvent; or (d) for acompound of Formula I wherein B is (CH₂)NR^(b)R^(c), reacting acorresponding compound having the Formula VI

with hydrazine; or (e) for a compound of Formula I where B is OR^(a),reacting a corresponding compound having the Formula VII

with a compound of the formula R^(a)-L², wherein L² represents a leavingatom or group, in the presence of a base; and removing any protectinggroup or groups and, if desired, forming a salt.